Amino alcohol derivatives

ABSTRACT

Compounds of formula (I) which exhibit excellent immune suppression activity, pharmacologically acceptable salts thereof, esters thereof or other derivatives:  
                 
 
     wherein R 1  and R 2  are a hydrogen atom, an amino protecting group; R 3  is a hydrogen atom, a hydroxy protecting group; R 4  is a lower alkyl group; n is an integer from 1 to 6; X is an ethylene group; Y is a C 1 -C 10  alkylene group, a C 1 -C 10  alkylene group substituted with 1 to 3 substituents selected from substituent group a and b; R 5  is an aryl group; R 6  and R 7  are a hydrogen atom, a group selected from substituent group a; with the proviso when R 5  is a hydrogen atom, Y is not a single bond or a straight chain C 1 -C 10  alkylene group.

[0001] This application is a divisional application of Ser. No.10/337,702 filed Jan. 7, 2003, pending, which is a continuation-in-partof International Application PCT/JP01/05988 filed Jul. 10, 2001 (notpublished in English).

BACKGROUND OF THE INVENTION

[0002] The present invention relates to amino alcohol derivatives havingexcellent immune suppression activity, pharmacologically acceptablesalts thereof, esters thereof or other derivatives thereof; topharmaceutical compositions containing said compounds as an activeingredient; to the use of said compounds in the preparation of saidpharmaceutical compositions; and to methods for prevention or treatmentof autoimmune diseases, which comprise administering a pharmacologicallyeffective amount of said compound to warm blooded animals in need ofsuch prevention or treatment.

[0003] In another aspect, the present invention relates to opticallyactive novel amino alcohol derivatives (particularly, optically active4,4-disubstituted oxazolidin-2-one derivatives), which are usefulsynthetic intermediates for the preparation of said amino alcoholderivatives or other medicaments.

[0004] In yet another aspect, the present invention relates to a novelprocesses for the excellent selective preparation of optically active2-substituted 2-amino-1,3-propanediol mono-ester derivatives, which areuseful synthetic intermediates for the preparation of said amino alcoholderivatives in optically active form.

[0005] Steroids or antiinflammatory drugs have been used as therapeuticagents for inflammatory responses caused by abnormal immunologicalresponses in diseases related to the immune system such as rheumatoidarthritis and other autoimmune diseases. However, these agents areagents that improve the symptoms, but they do not provide treatment ofthe causes.

[0006] Although abnormal immunological responses have also been reportedto contribute to the pathogenesis of diabetes mellitus and nephritis[Kidney International, 51, 94 (1997); Journal of Immunology, 157, 4691(1996)], no agents have ever been developed to improve the abnormalimmunological responses.

[0007] On the other hand, development of immune suppressors is importantfor prevention of immunological rejection occurring in organtransplantation or for the prevention or therapy of autoimmune diseases.Nevertheless, well known immunosuppressors such as cyclosporin A (CsA)and tacrolimus (TRL) are known to cause renal toxicity orhepatotoxicity. Although steroids have been administered together withimmunosuppressors in order to decrease such adverse effects of theimmunosuppressors, the immunosuppressing effects could not besatisfactorily elicited without the adverse events.

[0008] From these backgrounds, many attempts have been made to findcompounds exerting excellent immunosuppressing effects with lowtoxicity.

[0009] The following compounds are known as immunosuppressive agents:

[0010] (1) In the specification of WO94/08943 (EP627406) compounds offormula (a) are disclosed as immunosuppressive agents,

[0011] wherein R is a straight or branched carbon chain which may have,in the chain, a group selected from the group consisting of a doublebond, a triple bond, oxygen atom, sulfur atom, —N(R⁶)—(wherein R⁶ is ahydrogen atom), optionally substituted arylene, optionally substitutedheteroarylene or the like, and which may be substitued, at the chain endthereof, by optionally substituted aryl, optionally substitutedcycloalkyl, optionally substituted heteroaryl or the like; and R², R³,R⁴, R⁵ are the same or different and each represent a hydrogen atom, analkyl group or the like.

[0012] The compounds of formula (a) have two oxymethyl groups (—CH₂OR⁴and —CH₂OR⁵) as essential groups. The compounds of the presentinvention, however, have a —CH₂OR³ group and a lower alkyl group and aredifferent from the compounds of formula (a) in these substituents.

[0013] In said specification no typical compounds similar to thecompounds of formula (I) in the present invention are disclosed at all.Only the following two compounds of the compounds of formula (a) arehighly similar in chemical structure to the compounds of formula (I) inthe present invention:

[0014] (2) In the specification of WO96/06068 compounds of formula (b)are disclosed as immunosuppressive agents,

[0015] wherein R¹, R² and R³ each are a hydrogen atom or the like; W isa hydrogen atom, an alkyl group or the like; Z is a single bond or analkylene group; X is a hydrogen atom or an alkoxy group; Y is a hydrogenatom, an alkyl, alkoxy, acyl, acyloxy, amino, acylamino group or thelike.

[0016] The compounds of formula (b) essentially have a phenyl group as abasic skeleton. The compounds of formula (I) in the present inventionhave a thiophene group instead of the phenyl group of compounds offormula (b) and are different from the compounds of formula (b) in thebasic skeleton.

[0017] In said specification no typical compounds similar to thecompounds of formula (I) in the present invention are disclosed at all.Only the following three compounds of the compounds of formula (b) arehighly similar in chemical structure to the compounds of formula (I) inthe present invention:

[0018] (3) In the specification of WO98/45249 compounds of formula (c)are disclosed as immunosuppressive agents,

[0019] wherein R¹, R², R³, R⁴ are the same or different and eachrepresent a hydrogen atom or an acyl group.

[0020] The compounds of formula (c) have two oxymethyl groups (—CH₂OR³and —CH₂OR⁴) as essential substituent groups. The compounds of thepresent invention have a —CH₂OR³ group and a lower alkyl group and aredifferent from the compounds of formula (a) in these substituents. Thecompounds of formula (c) have a phenyl group between —(CH₂)₂— and—CO(CH₂)₄— as a basic skeleton. The compounds of formula (I) in thepresent invention have a thiophene group instead of the phenyl group ofthe compounds of formula (c). The present compounds of formula (I) arealso different from the compounds of formula (c) in the basic skeleton.The compounds of formula (c) have only a phenyl group at the end of—CO—(CH₂)₄— group. The compounds of formula (I) in the present inventionmay have a phenyl group, a cycloalkyl group or a heterocyclic group atthe end of the molecule.

[0021] In said specification no typical compounds similar in chemicalstructure to the compounds of formula (I) in the present invention aredisclosed at all. Only the following three compounds of the compounds offormula (c) are highly similar in chemical structure to the compounds offormula (I) in the present invention:

[0022] On the other hand, various optically active substituted aminoacid and substituted amino alcohol derivatives (particularlyα-substituted amino acid and α-substituted amino alcohol derivatives)exhibit biological activity; are partial components of natural productsand pharmaceutical agents; and are important synthetic intermediates.For example, α-methyl-α-vinyl amino acids are useful as an amino aciddecarboxylase inhibitor; α-ethynyl-α-methyl amino acids are useful as aglutamic acid decarboxylase inhibitor; ISP-1 (Myriocin), which isisolated from metabolites of Isalia sinclairii, has immune suppressionactivity; and Conagenine and the like participate in the regulation ofimmune response through T-cells. From these results, α-substituted aminoacid and amino alcohol derivatives are very interesting compounds as apartial component of natural products having biological activity, in thefield of biochemistry and in the field of organic synthesis.

[0023] These α-substituted amino acid and amino alcohol derivatives havean asymmetric center(s) and an efficient process for the preparation ofone enantiomer thereof has been expected.

[0024] There are a few reports of processes for the preparation ofoptically active substituted amino acid and amino alcohol derivativesand a few reports of synthetic examples of optically active aminoalcohol derivatives such as optically active 4,4-disubstitutedoxazolizin-2-one derivatives, which are useful synthetic intermediatesof optically active substituted amino acid and amino alcohol derivativesdescribed hereinbefore. For example, there are reports by C. Cativielaet al., Tetrahedron: Asymmetry, 9, 3517 (1998) and Synthesis ofOptically active α-amino acids (Pergamon Press) R. M. Williams et al andthe methods are largely classified into two groups for preparation ofthem. The one is a diasteroselective alkylation method using anassisting group for asymmetric synthesis, a typical example being amethod described by Seebach in Helv. Chim. Acta., 71, 224 (1988) or thesynthesis of α-substituted serine derivatives which are obtained by ahighly diastereoselective aldol reaction using chiral bis-lactam ethercarboxylic acid esters and Mg(II) and Sn(II) type Lewis acids describedby Nagao and Sano et al. in Tetrahedron Lett., 36, 2097 (1995) andTetrahedron Lett., 36, 4101 (1995). The other one is a synthesis ofα-substituted serine derivatives which are obtained by enantioselectiveenzymatic hydrolysis of prochiral σ-symmetry diester compounds(α-substituted-α-protected malonic acid diesters) and is described byNagao, Tamai et al., in Chemistry Lett., 239 (1989) and Chemistry Lett.,2381 (1994).

[0025] The former method has multi-step reactions and needs astoichiometric asymmetric source. The latter method has a reduction stepand cannot be used when a compound has a group unstable under reductionconditions.

[0026] There are some reports described hereinbefore but, however thepractically useful methods are limited. In general, one enantiomer isoptically resolved from a racemic mixture. In this case there is aproblem that the total yield of the desired compound is low.

BRIEF SUMMARY OF THE INVENTION

[0027] The present inventors have performed painstaking research tocomplete these objectives, and found that the amino alcohol derivatives(I) of the present invention exert an excellent immunosuppressive effectwith low toxicity and are useful as therapeutic agents for autoimmunediseases such as systemic lupus erythematosus, rheumatoid arthritis,polymyositis, dermatomyositis, Behcet's syndrome, Chron disease,ulcerative colitis, autoimmune hepatitis, aplastic anemia, scleoderma,idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia,multiple sclerosis, autoimmune bullosis, vulgarity psoriasis, vasculitissyndrome, Wegener's granuloma, uveitis, cryptogenic fibrosingalveolitis, Goodpasture's syndrome, sarcoidosis, allergic granulomatousangitis, bronchial asthma, myocarditis, cardiomyopathy, aortic archsyndrome, myocardial postinfarction syndrome, primary pulmonaryhypertension, minimal change nephrotic syndrome, membranous nephropathy,membranoproliferative glomerulonephritis, focal glomerular sclerosis,crescent glomerulonephritis, myasthenia gravis, inflammatory neuropathy,atopic dermatitis, chronic actinic dermatitis, acute polyarthritis,Sydenhan chorea disease, progressive systemic sclerosis, adult onsettype diabetes mellitus, insulin dependent diabetes mellitus, juvenilediabetes, atherosclerosis, glomerular nephritis, tuburointerstitialnephritis, primary biliary cirrhosis, primary sclerosing cholangitis,fulminant hepatic failure, viral hepatitis, GVHD, immunologicalrejection following organ transplantation, contact dermatitis, sepsis orother immunology related diseases, and completed the present invention.

[0028] The present invention provides amino alcohol derivatives whichexhibit low toxicity and excellent immune suppression activity,pharmacologically acceptable salts thereof, esters thereof or otherderivatives thereof.

[0029] In another aspect, the present invention provides pharmaceuticalcompositions containing said amino alcohol derivatives, apharmacologically acceptable salt thereof, an ester thereof, or otherderivative thereof as an active ingredient; the use of said compounds inthe preparation of said pharmaceutical compositions; or methods forprevention or treatment of the diseases described hereinbefore such asautoimmune diseases and the like, which comprise administering apharmacologically effective amount of said compound to warm bloodedanimals (e.g. humans) in need of such prevention or treatment.

[0030] The inventors have made a great effort to solve the problemsdescribed hereinbefore about a process for the preparation of opticallyactive amino alcohol derivatives and intermediates thereof. They havefound that optically active novel amino alcohol derivatives of formulae(La) and (Lb) (especially 4,4-disubstituted oxazolizin-2-onederivatives) can be obtained more easily than by conventional methodsand said derivatives are useful synthetic intermediates for thepreparation of optically active substituted amino acid and substitutedamino alcohol derivatives and medicaments.

[0031] In addition they have also made a great effort to find a processfor the selective preparation of the optically active amino alcoholcompounds of formulae (La) and (Lb). They found that optically active2-substituted 2-amino-1,3-propanediol mono-ester derivatives of formulae(XLIVa) or (XLIVb) are useful intermediate for the preparation and saidcompounds of formulae (XLIVa) and (XLIVb) can easily be obtained from2-substituted 2-amino-1,3-propanediol derivatives of formula (XLII)using carboxylic acid vinyl esters of formula (XLIII) in the presence oflipase through selective acylation of one hydroxyl group in good yield.

DETAILED DESCRIPTION OF THE INVENTION

[0032] (1) The present invention comprises amino alcohol derivatives ofthe following formula (I), pharmacologically acceptable salts thereof,esters thereof or other derivatives thereof:

[0033] wherein

[0034] R¹ and R² are the same or different and each represents ahydrogen atom or an amino protecting group;

[0035] R³ represents a hydrogen atom or a hydroxy protecting group;

[0036] R⁴ represents a lower alkyl group;

[0037] n represents an integer from 1 to 6;

[0038] X represents an ethylene group, a vinylene group, an ethynylenegroup, a group of formula -D-CH₂— (wherein D represents a carbonylgroup, a group of formula —CH(OH)—, an oxygen atom, a sulfur atom, or anitrogen atom), an aryl group, or an aryl group substituted with 1 to 3substituents selected from substituent group a;

[0039] Y represent a single bond, a C₁-C₁₀ alkylene group, a C₁-C₁₀alkylene group substituted with 1 to 3 substituents selected fromsubstituent groups a and b, a C₁-C₁₀ alkylene group which has an oxygenatom or a sulfur atom in said carbon chain or at the end of said carbonchain, or a C₁-C₁₀ alkylene group which is substituted with 1 to 3substituents selected from substituent groups a and b and has an oxygenatom or a sulfur atom in said carbon chain or at the end of said carbonchain;

[0040] R⁵ represents a hydrogen atom, a cycloalkyl group, an aryl group,a heterocyclic group, a cycloalkyl group substituted with 1 to 3substituents selected from substituent groups a and b, an aryl groupsubstituted with 1 to 3 substituents selected from substituent groups aand b, or a heterocyclic group substituted with 1 to 3 substituentsselected from substituent groups a and b;

[0041] R⁶ and R⁷ are the same or different and each represents ahydrogen atom or a group selected from substituent group a;

[0042] with the proviso that when R⁵ is a hydrogen atom, Y is not asingle bond or a straight C₁-C₁₀ alkylene group;

[0043] substituent group a consists of a halogen atom, a lower alkylgroup, a halognated lower alkyl group, a lower alkoxy group, a loweralkylthio group, a carboxyl group, a lower alkoxycarbonyl group,.ahydroxyl group, a lower aliphatic acyl group, an amino group, a monolower alkylamino group, a di lower alkylamino group, a lower aliphaticacylamino group, a cyano group, and a nitro group;

[0044] substituent group b consists of a cycloalkyl group, an arylgroup, a heterocyclic group, a cycloalkyl group substituted with 1 to 3substituents selected from substituent group a, an aryl groupsubstituted with 1 to 3 substituents selected from substituent group a,and a heterocyclic group substituted with 1 to 3 substituents selectedfrom substituent group a.

[0045] Among these compounds described in (1), preferred compoundsinclude:

[0046] (2) a compound according to (1) wherein said compound has aformula (Ia), a pharmacologically acceptable salt thereof, an esterthereof or other derivative thereof;

[0047] (3) a compound according to (1) wherein said compound has aformula (Ib), a pharmacologically acceptable salt thereof, an esterthereof or other derivative thereof,

[0048] (4) a compound according to any one of (1) to (3) wherein R¹ andR² are the same or different and each is a hydrogen atom, a loweralkoxycarbonyl group, an aralkyloxycarbonyl group, or anarakyloxycarbonyl group substituted with 1 to 3 substituents selectedfrom substituent group a, or a pharmacologically acceptable saltthereof;

[0049] (5) a compound according to any one of (1) to (3) wherein each ofR¹ and R² is a hydrogen atom, or a pharmacologically acceptable saltthereof;

[0050] (6) a compound according to any one of (1) to (5) wherein R³ is ahydrogen atom, a lower alkyl group, a lower aliphatic acyl group, anaromatic acyl group or an aromatic acyl group substituted with 1 to 3substituents selected from substituent group a, or a pharmacologicallyacceptable salt thereof;

[0051] (7) a compound according to any one of (1) to (5) wherein R³ is ahydrogen atom, or a pharmacologically acceptable salt thereof;

[0052] (8) a compound according to any one of (1) to (7) wherein R⁴ is aC₁-C₄ alkyl group, or a pharmacologically acceptable salt thereof;

[0053] (9) a compound according to any one of (1) to (7) wherein R⁴ is aC₁-C₂ alkyl group, or a pharmacologically acceptable salt thereof;

[0054] (10) a compound according to any one of (1) to (7) wherein R⁴ isa methyl group, or a pharmacologically acceptable salt thereof;

[0055] (11) a compound according to any one of (1) to (10) wherein n is2 or 3, or a pharmacologically acceptable salt thereof;

[0056] (12) a compound according to any one of(1) to (10) wherein n is2, or a pharmacologically acceptable salt thereof;

[0057] (13) a compound according to any one of (1) to (12) wherein X isan ethylene group, an ethynylene group, an aryl group, or an aryl groupsubstituted with 1 to 3 substituents selected from substituent group a,or a pharmacologically acceptable salt thereof;

[0058] (14) a compound according to any one of (1) to (12) wherein X isan ethylene group, or a pharmacologically acceptable salt thereof;

[0059] (15) a compound according to any one of (1) to (12) wherein X isan ethynylene group, or a pharmacologically acceptable salt thereof;

[0060] (16) a compound according to any one of (1) to (12) wherein X isa group of formula -D-CH₂—, or a pharmacologically acceptable saltthereof;

[0061] (17) a compound according to any one of (1) to (12) wherein X isa group of formula -D-CH₂— (wherein D represents a carbonyl group or agroup of formula —CH(OH)—), or a pharmacologically acceptable saltthereof;

[0062] (18) a compound according to any one of (1) to (17) wherein Y isa C₁-C₁₀ alkylene group, or a C₁-C₁₀ alkylene group substituted with 1to 3 substituents selected from substituent groups a and b, or apharmacologically acceptable salt thereof;

[0063] (19) a compound according to any one of (1) to (17) wherein Y isa C₁-C₆ alkylene group, or a C₁-C₆ alkylene group substituted with 1 to3 substituents selected from substituent groups a and b, or apharmacologically acceptable salt thereof;

[0064] (20) a compound according to any one of (1) to (17) wherein Y isan ethylene group, a trimethylene group, a tetramethylene group, anethylene group substituted with 1 to 3 substituents selected fromsubstituent groups a and b, a trimethylene group substituted with 1 to 3substituents selected from substituent groups a and b, or atetramethylene group substituted with 1 to 3 substituents selected fromsubstituent groups a and b, or a pharmacologically acceptable saltthereof;

[0065] (21) a compound according to any one of (1) to (17) wherein Y isan ethylene group, a trimethylene group, or a tetramethylene group, or apharmacologically acceptable salt thereof;

[0066] (22) a compound according to any one of (1) to (17) wherein Y isan ethylene group or a trimethylene group, or a pharmacologicallyacceptable salt thereof;

[0067] (23) a compound according to any one of (1) to (17) wherein Y isa C₁-C₁₀ alkylene group which has an oxygen atom or a sulfur atom insaid carbon chain or at the end of said carbon chain, or a C₁-C₁₀alkylene group which is substituted with 1 to 3 substituents selectedfrom substituent groups a and b and has an oxygen atom or a sulfur atomin said carbon chain or at the end of said carbon chain, or apharmacologically acceptable salt thereof;

[0068] (24) a compound according to any one of (1) to (17) wherein Y isa C₁-C₁₀ alkylene group which has an oxygen atom or a sulfur atom insaid carbon chain or at the end of said carbon chain, or apharmacologically acceptable salt thereof;

[0069] (25) a compound according to any one of (1) to (17) wherein Y isa C₁-C₁₀ alkylene group which has an oxygen atom in said carbon chain orat the end of said carbon chain, or a pharmacologically acceptable saltthereof;

[0070] (26) a compound according to any one of (1) to (17) wherein Y isa C₁-C₆ alkylene group which has an oxygen atom in said carbon chain orat the end of said carbon chain, or a pharmacologically acceptable saltthereof,

[0071] (27) a compound according to any one of (1) to (17) wherein Y isa group of formula —O—CH₂—, —O—(CH₂)₂—, —O—(CH₂)₃—, —CH₂—O—, —(CH₂)₂—O—,or —(CH₂)₃—O—, or pharmacologically acceptable salt thereof;

[0072] (28) a compound according to any one of (1) to (17) wherein Y isa group of formula —CH₂—O—, or a pharmacologically acceptable saltthereof;

[0073] (29) a compound according to any one of (1) to (17) wherein Y isa group of formula —O—(CH₂)₂— or —(CH₂)₂—O—, or a pharmacologicallyacceptable salt thereof;

[0074] (30) a compound according to any one of (1) to (29) wherein R⁵ isa hydrogen atom, or a pharmacologically acceptable salt thereof;

[0075] (31) a compound according to any one of (1) to (29) wherein R⁵ isa cycloalkyl group, a heterocyclic group, a cycloalkyl group substitutedwith 1 to 3 substituents selected from substituent groups a and b, or aheterocyclic group substituted with 1 to 3 substituents selected fromsubstituent groups a and b, or a pharmacologically acceptable saltthereof;

[0076] (32) a compound according to any one of (1) to (29) wherein R⁵ isa cycloalkyl group or a cycloalkyl group substituted with 1 to 3substituents selected from substituent groups a and b, or apharmacologically acceptable salt thereof;

[0077] (33) a compound according to any one of (1) to (29) wherein R⁵ isa cycloalkyl group, or a pharmacologically acceptable salt thereof;

[0078] (34) a compound according to any one of (1) to (29) wherein R⁵ isa cyclohexyl group, or a pharmacologically acceptable salt thereof;

[0079] (35) a compound according to any one of (1) to (29) wherein R⁵ isan aryl group or an aryl group substituted with 1 to 3 substituentsselected from substituent groups a and b, or a pharmacologicallyacceptable salt thereof;

[0080] (36) a compound according to any one of (1) to (29) wherein R⁵ isan aryl group or an aryl group substituted with 1 to 3 substituents(said substituent is selected from the group consisting of a halogenatom, a lower alkyl group, a halogenated lower alkyl group, a loweralkoxy group, a lower alkylthio group and a lower aliphatic acyl group),or a pharmacologically acceptable salt thereof;

[0081] (37) a compound according to any one of (1) to (29) wherein Rs isan aryl group or an aryl group substituted with 1 to 3 substituents(said substituent is selected from the group consisting of a halogenatom, a lower alkyl group, a halogenated lower alkyl group, a loweralkoxy group, and a lower aliphatic acyl group), or a pharmacologicallyacceptable salt thereof;

[0082] (38) a compound according to any one of (1) to (29) wherein R⁵ isa phenyl group or a phenyl group substituted with 1 to 3 substituents(said substituent is selected from the group consisting of a halogenatom, a lower alkyl group, a halogenated lower alkyl group, a loweralkoxy group, and a lower aliphatic acyl group), or a pharmacologicallyacceptable salt thereof;

[0083] (39) a compound according to any one of (1) to (29) wherein R⁵ isa phenyl group or a phenyl group substituted with 1 to 3 substituents(said substituent is selected from the group consisting of a fluorineatom, a chlorine atom, a methyl, trifluoromethyl, methoxy, and acetylgroup), or a pharmacologically acceptable salt thereof;

[0084] (40) a compound according to any one of (1) to (29) wherein R⁵ isa phenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl,3,5-dichlorophenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl,3,5-dimethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl,3,4-ditrifluoromethylphenyl, 3,5-ditrifluoromethylphenyl,3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl,3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3-acetylphenyl, or4-acetylphenyl, or a pharmacologically acceptable salt thereof;

[0085] (41) a compound according to any one of (1) to (40) wherein R⁶and R⁷ are the same or different and each is a hydrogen atom, a halogenatom, a lower alkyl group, a halogenated lower alkyl group, a loweralkoxy group or a lower alkylthio group, or a pharmacologicallyacceptable salt thereof;

[0086] (42) a compound according to any one of (1) to (40) wherein eachof R⁶ and R⁷ is a hydrogen atom, or a pharmacologically acceptable saltthereof;

[0087] (43) a compound according to (1) wherein said compound isselected the following compounds, a pharmacologically acceptable saltthereof, an ester thereof or other derivative thereof:

[0088]2-amino-2-methyl-4-[5-(6-cyclohexylhexyl)thiophen-2-yl]butan-1-ol,

[0089]2-amino-2-methyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol,

[0090]2-amino-2-methyl-4-[5-(4-cyclohexylbutyl)thiophen-2-yl]butan-1-ol,

[0091]2-amino-2-methyl-4-[5-(6-cyclohexylhex-1-ynyl)thiophen-2-yl]butan-1-ol,

[0092]2-amino-2-methyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol,

[0093]2-amino-2-methyl-4-[5-(4-cyclohexylbut-1-ynyl)thiophen-2-yl]butan-1-ol,

[0094]2-amino-2-methyl-4-[5-(6-cyclohexylhexanoyl)thiophen-2-yl]butan-1-ol,

[0095]2-amino-2-methyl-4-[5-(5-cyclohexylpentanoyl)thiophen-2-yl]butan-1-ol,

[0096]2-amino-2-methyl-4-[5-(4-cyclohexylbutanoyl)thiophen-2-yl]butan-1-ol,

[0097] 2-amino-2-ethyl-4-[5-(6-cyclohexylhexyl)thiophen-2-yl]butan-1-ol,

[0098]2-amino-2-ethyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol,

[0099] 2-amino-2-ethyl-4-[5-(4-cyclohexylbutyl)thiophen-2-yl]butan-1-ol,

[0100]2-amino-2-ethyl-4-[5-(6-cyclohexylhex-1-ynyl)thiophen-2-yl]butan-1-ol,

[0101]2-amino-2-ethyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol,

[0102]2-amino-2-ethyl-4-[5-(4-cyclohexylbut-1-ynyl)thiophen-2-yl]butan-1-ol,

[0103]2-amino-2-ethyl-4-[5-(6-cyclohexylhexanoyl)thiophen-2-yl]butan-1-ol,

[0104]2-amino-2-ethyl-4-[5-(5-cyclohexylpentanoyl)thiophen-2-yl]butan-1-ol,

[0105]2-amino-2-ethyl-4-[5-(4-cyclohexylbutanoyl)thiophen-2-yl]butan-1-ol,

[0106] 2-amino-2-methyl-4-[5-(6-phenylhexyl)thiophen-2-yl]butan-1-ol,

[0107] 2-amino-2-methyl-4-[5-(5-phenylpentyl)thiophen-2-yl]butan-1-ol,

[0108] 2-amino-2-methyl-4-[5-(4-phenylbutyl)thiophen-2-yl]butan-1-ol,

[0109]2-amino-2-methyl-4-[5-(6-phenylhex-1-ynyl)thiophen-2-yl]butan-1-ol,

[0110]2-amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol,

[0111]2-amino-2-methyl-4-[5-(4-phenylbut-1-ynyl)thiophen-2-yl]butan-1-ol,

[0112] 2-amino-2-methyl-4-[5-(6-phenylhexanoyl)thiophen-2-yl]butan-1-ol,

[0113]2-amino-2-methyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-ol,

[0114] 2-amino-2-methyl-4-[5-(4-phenylbutanoyl)thiophen-2-yl]butan-1-ol,

[0115]2-amino-2-methyl-4-[5-(5-cyclohexyloxypent-1-ynyl)thiophen-2-yl]butan-1-ol,

[0116]2-amino-2-methyl-4-[5-(4-cyclohexyloxybut-1-ynyl)thiophen-2-yl]butan-1-ol,

[0117]2-amino-2-methyl-4-[5-(3-cyclohexyloxypropynyl)thiophen-2-yl]butan-1-ol,

[0118]2-amino-2-methyl-4-[5-(5-cyclohexyloxypentyl)thiophen-2-yl]butan-1-ol,

[0119]2-amino-2-methyl-4-[5-(4-cyclohexyloxybutyl)thiophen-2-yl]butan-1-ol,

[0120]2-amino-2-methyl-4-[5-(3-cyclohexyloxypropyl)thiophen-2-yl]butan-1-ol,

[0121]2-amino-2-methyl-4-[5-(5-cyclohexyloxypentanoyl)thiophen-2-yl]butan-1-ol,

[0122]2-amino-2-methyl-4-[5-(4-cyclohexyloxybutanoyl)thiophen-2-yl]butan-1-ol,

[0123]2-amino-2-methyl-4-[5-(3-cyclohexyloxypropanoyl)thiophen-2-yl]butan-1-ol,

[0124]2-amino-2-methyl-4-[5-(5-phenoxypent-1-ynyl)thiophen-2-yl]butan-1-ol,

[0125]2-amino-2-methyl-4-[5-(4-phenoxybut-1-ynyl)thiophen-2-yl]butan-1-ol,

[0126]2-amino-2-methyl-4-[5-(3-phenoxypropynyl)thiophen-2-yl]butan-1-ol,

[0127] 2-amino-2-methyl-4-[5-(5-phenoxypentyl)thiophen-2-yl]butan-1-ol,

[0128] 2-amino-2-methyl-4-[5-(4-phenoxybutyl)thiophen-2-yl]butan-1-ol,

[0129] 2-amino-2-methyl-4-[5-(3-phenoxypropyl)thiophen-2-yl]butan-1-ol,

[0130]2-amino-2-methyl-4-[5-(5-phenoxypentanoyl)thiophen-2-yl]butan-1-ol,

[0131]2-amino-2-methyl-4-[5-(4-phenoxybutanoyl)thiophen-2-yl]butan-1-ol,

[0132]2-amino-2-methyl-4-[5-(3-phenoxypropanoyl)thiophen-2-yl)butane-1-ol,

[0133]2-amino-2-methyl-4-[5-(4-benzyloxyphenyl)thiophen-2-yl]butan-1-ol,

[0134]2-amino-2-methyl-4-[5-(4-cyclohexylmethoxyphenyl)thiophen-2-yl]butan-1-ol,

[0135]2-amino-2-methyl-4-[5-(4-cyclohexylethoxyphenyl)thiophen-2-yl]butan-1-ol,

[0136]2-amino-2-methyl-4-[5-(3-cyclohexylmethoxypropynyl)thiophen-2-yl]butan-1-ol,

[0137]2-amino-2-methyl-4-[5-(3-cyclohexylmethoxypropyl)thiophen-2-yl]butan-1-ol,and

[0138]2-amino-2-methyl-4-[5-(3-cyclohexylmethoxypropanoyl)thiophen-2-yl]butan-1-ol.

[0139] (44) a compound according-to (1) wherein said compound isselected the following compounds, a pharmacologically acceptable saltthereof, an ester thereof or other derivative thereof:

[0140]2-amino-2-methyl-4-[5-(4-cyclohexylbutyl)thiophen-2-yl]butan-1-ol,

[0141]2-amino-2-methyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol,

[0142] 2-amino-2-methyl-4-[5-(5-phenylpentyl)thiophen-2-yl]butan-1-ol,

[0143]2-amino-2-methyl-4-[5-(4-cyclohexyloxybutyl)thiophen-2-yl]butan-1-ol,

[0144]2-amino-2-methyl-4-{5-[4-(4-fluorophenoxy)butyl]thiophen-2-yl}butan-1-ol,

[0145]2-amino-2-methyl-4-{5-[4-(4-methoxyphenoxy)butyl]thiophen-2-yl}butan-1-ol,

[0146] 2-amino-2-methyl-4-[5-(4-benzyloxybutyl)thiophen-2-yl]butan-1-ol,

[0147]2-amino-2-methyl-4-[5-(4-cyclohexylbut-1-ynyl)thiophen-2-yl]butan-1-ol,

[0148]2-amino-2-methyl-4-[5-(4-phenylbut-1-ynyl)thiophen-2-yl]butan-1-ol,

[0149]2-amino-2-methyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol,

[0150]2-amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol,

[0151]2-amino-2-methyl-4-{5-[5-(4-fluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0152]2-amino-2-methyl-4-{5-[5-(4-methoxyphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0153]2-amino-2-methyl-4-{5-[3-(4-methylcyclohexyloxy)propynyl]thiophen-2-yl}butan-1-ol,

[0154]2-amino-2-methyl-4-{5-[3-(4-methylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0155]2-amino-2-methyl-4-{5-[3-(4-ethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0156]2-amino-2-methyl-4-{5-[3-(4-methylthiophenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0157]2-amino-2-methyl-4-[5-(4-cyclohexyloxybut-1-ynyl)thiophen-2-yl]butan-1-ol,

[0158]2-amino-2-methyl-4-{5-[4-(4-fluorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0159]2-amino-2-methyl-4-{5-[4-(4-methylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0160]2-amino-2-methyl-4-[5-(3-cyclohexylmethoxypropynyl)thiophen-2-yl]butan-1-ol,

[0161]2-amino-2-methyl-4-[5-(4-phenylmethoxybut-1-ynyl)thiophen-2-yl]butan-1-ol,

[0162]2-amino-2-methyl-4-[5-(4-cyclohexylbutanoyl)thiophen-2-yl]butan-1-ol,

[0163] 2-amino-2-methyl-4-[5-(4-phenylbutanoyl)thiophen-2-yl]butan-1-ol,

[0164]2-amino-2-methyl-4-[5-(5-cyclohexylpentanoyl)thiophen-2-yl]butan-1-ol,

[0165]2-amino-2-methyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-ol,

[0166]2-amino-2-methyl-4-{5-[5-(4-fluorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

[0167]2-amino-2-ethyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol,

[0168]2-amino-2-ethyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol,

[0169]2-amino-2-ethyl-4-[5-(5-cyclohexylpentanoyl)thiophen-2-yl]butan-1-ol,

[0170]2-amino-2-methyl-4-{5-[3-(4-chlorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0171]2-amino-2-methyl-4-{5-[3-(3-methylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0172]2-amino-2-methyl-4-{5-[3-(3,4-dimethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0173]2-amino-2-methyl-4-{5-[3-(3-methoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0174]2-amino-2-methyl-4-{5-[3-(3,4-dimethoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0175]2-amino-2-methyl-4-{5-[3-(3,5-dimethoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0176]2-amino-2-methyl-4-{5-[3-(3-acetylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,and

[0177]2-amino-2-methyl-4-{5-[3-(4-acetylphenoxy)propynyl]thiophen-2-yl}butan-1-ol.

[0178] Preferred compounds of formula (I) also include ones comprising acombination of one group selected from each of the groups consisting of(2) and (3); (4) and (5); (6) and (7); (8) to (10); (11) and (12); (13)to (17); (18) to (29); (30) to (40); and (41) and (42).

[0179] (45) The present invention includes an optically active aminoalcohol derivative of formula (La) or (Lb):

[0180] wherein

[0181] R¹ and R² are the same or different and each represents ahydrogen atom or an amino protecting group;

[0182] R^(3a) represents a hydrogen atom or a hydroxy protecting groupor when R¹ is a hydrogen atom, R² and R^(3a) taken together form a groupof formula —(C═O)—;

[0183] R^(4a) represents a C₁-C₂₀ alkyl group, a C₂-C₂₀ alkyl groupinterrupted with a heteroatom(s), a C₁-C₂₀ alkyl group substituted withan aryl group(s) or a heteroaryl group(s), a C₂-C₂₀ alkynyl group, aC₃-C₂₀ alkynyl group interrupted with a heteroatom(s), a C₂-C₂₀ alkynylgroup substituted with an aryl group(s) or a heteroaryl group(s), aC₂-C₂₀ alkenyl group, a C₃-C₂₀ alkenyl group interrupted with aheteroatom(s), a C₂-C₂₀ alkenyl group substituted with an aryl group(s)or a heteroaryl group(s), a C₂-C₂₀ alkyl group which is substituted withan aryl group(s) or a heteroaryl group(s) and interrupted with aheteroatom(s), or a cycloalkyl group;

[0184] m represent an integer from 0 to 4;

[0185] Ar represents an aryl group, a heteroaryl group, an aryl groupsubstituted with 1 to 5 substituents selected from substituent group a,a heteroaryl group substituted with 1 to 5 substituents selected fromsubstituent group a, with the proviso that when Ar is an aryl group, R¹is not a hydrogen atom and R² and/or R^(3a) do not represent a hydrogenatom;

[0186] substituent group a represents a halogen atom, a lower alkylgroup, a halogenated lower alkyl group, a lower alkoxy group, a loweralkylthio group, a carboxyl group, a lower alkoxycarbonyl group, ahydroxyl group, a lower aliphatic acyl group, an amino group, a lowermono-alkylamino group, a lower di-alkylamino group, a lower aliphaticacylamino group, a cyano group, and a nitro group.

[0187] Preferred compounds of formula (La) or (Lb) include the followingcompounds:

[0188] (46) a compound according to (45) wherein said compound hasformula (La);

[0189] (47) a compound according to (45) or (46) wherein R¹ is ahydrogen atom;

[0190] (48) a compound according to any one of (45) to (47) wherein R²and R³a taken together form a group of formula —(C═O)—;

[0191] (49) a compound according to any one of (45) to (47) whereinR^(3a) is a hydrogen atom;

[0192] (50) a compound according to any one of (45) to (49) whereinR^(4a) is a C₁-C₁₀ alkyl group, a C₂-C₁₀ alkyl group interrupted with aheteroatom(s), a C₁-C₁₀ alkyl group substituted with an aryl group(s) ora heteroaryl group(s), a C₂-C₁₀ alkynyl group, a C₃-C₁₀ alkynyl groupinterrupted with a heteroatom(s), a C₂-C₁₀ alkynyl group substitutedwith an aryl group(s) or a heteroaryl group(s), a C₂-C₁₀ alkenyl group,a C₃-C₁₀ alkenyl group interrupted with a heteroatom(s), a C₂-C₁₀alkenyl group substituted with an aryl group(s) or a heteroarylgroup(s), a C₂-C₁₀ alkyl group which is substituted with an arylgroup(s) or a heteroaryl group(s) and interrupted with a heteroatom(s),or a C₅-C₁₀ cycloalkyl group;

[0193] (51) a compound according to any one of (45) to (49) whereinR^(4a) is a C₁-C₁₀ alkyl group, a C₂-C₁₀ alkyl group interrupted with aheteroatom(s), a C₁-C₁₀ alkyl group substituted with an aryl group(s) ora heteroaryl group(s), a C₂-C₁₀ alkynyl group, a C₂-C₁₀ alkenyl group,or a C₅-C₁₀ cycloalkyl group;

[0194] (52) a compound according to any one of (45) to (49) whereinR^(4a) is a C₁-C₁₀ alkyl group;

[0195] (53) a compound according to any one of (45) to (49) wherein R⁴³is a C₁-C₆ alkyl group;

[0196] (54) a compound according to any one of (45) to (49) whereinR^(4a) is a methyl group or an ethyl group;

[0197] (55) a compound according to any one of (45) to (54) wherein Aris a phenyl, furyl, thienyl or benzothienyl group, said groupsoptionally being substituted with 1 to 4 substituents selected fromsubstituent group a;

[0198] (56) a compound according to any one of (45) to (54) wherein Aris a thienyl group or a thienyl group substituted with 1 to 4substituents selected from substituent group a;

[0199] (57) a compound according to any one of (45) to (54) wherein Aris a benzothienyl group or a benzothienyl group substituted with 1 to 4substituents selected from substituent group a;

[0200] (58) a compound according to (45) to (57) wherein m is 0;

[0201] (59) a compound according to any one of (45) to (57) whereinsubstituent group a is a halogen atom, a hydroxyl group, a lower alkylgroup, a halogenated lower alkyl group, a lower alkoxy group, a carboxylgroup, a lower aliphatic acyl group, a lower aliphatic acylamino group,an amino group, a cyano group, or a nitro group;

[0202] (60) The present invention relates to a process for thepreparation of a compound of a formula (XLIVa) or (XLIVb)

[0203] [wherein:

[0204] R¹ and R² are the same or different and each represents ahydrogen atom or an amino protecting group;

[0205] R^(4a) represents a C₁-C₂₀ alkyl group, a C₂-C₂₀ alkyl groupinterrupted with a heteroatom(s), a C₁-C₂₀ alkyl group substituted withan aryl group(s) or a heteroaryl group(s), a C₂-C₂₀ alkynyl group, aC₃-C₂₀ alkynyl group interrupted with a heteroatom(s), a C₂-C₂₀ alkynylgroup substituted with an aryl group(s) or a heteroaryl group(s), aC₂-C₂₀ alkenyl group, a C₃-C₂₀ alkenyl group interrupted with aheteroatom(s), a C₂-C₂₀ alkenyl group substituted with an aryl group(s)or a heteroaryl group(s), a C₂-C₂₀ alkyl group which is substituted withan aryl group(s) or a heteroaryl group(s) and interrupted with aheteroatom(s), or a cycloalkyl group; and

[0206] R¹ has the same meaning as that indicated above for R^(4a).].

[0207] The process comprises a selective acylation reaction-of onehydroxyl group of a 2-substituted 2-amino-1,3-propanediol derivative offormula (XLII)

[0208] [wherein R¹, R² and R^(4a) are defined in above.]

[0209] with a carboxylic acid ester derivative of formula (XLIII)

R¹¹COOCH═CH₂   (XLIII)

[0210] [wherein R¹¹ is defined in above.]

[0211] in the presence of a lipase to afford a 2-substituted2-amino-1,3-propanediol mono-ester derivative of formula (XLIVa) or(XLIVb).

[0212] (61) a process for preparation according to (60) wherein one ofR¹ and R² is a hydrogen atom and the other one is an amino protectinggroup;

[0213] (62) a process for preparation according to (60) or (61) whereinR^(4a) is a C₁-C₁₀ alkyl group, a C₂-C₁₀ alkyl group interrupted with aheteroatom(s), a C₁-C₁₀ alkyl group substituted with an aryl group(s) ora heteroaryl group(s), a C₂-C₁₀ alkynyl group, a C₃-C₁₀ alkynyl groupinterrupted with a heteroatom(s), a C₂-C₁₀ alkynyl group substitutedwith an aryl group(s) or a heteroaryl group(s), a C₂-C₁₀ alkenyl group,a C₃-C₁₀ alkenyl group interrupted with a heteroatom(s), a C₂-C₁₀alkenyl group substituted with an aryl group(s) or a heteroarylgroup(s), a C₂-C₁₀ alkyl group which is substituted with an arylgroup(s) or a heteroaryl group(s) and interrupted with a heteroatom(s),or a C₅-C₁₀ cycloalkyl group;

[0214] (63) a process for preparation according to (60) or (61) whereinR^(4a) is a C₁-C₁₀ alkyl group, a C₂-C₁₀ alkyl group interrupted with aheteroatom(s), a C₁-C₁₀ alkyl group substituted with an aryl group(s) ora heteroaryl group(s), a C₂-C₁₀ alkynyl group, a C₂-C₁₀ alkenyl group,or a C₅-C₁₀ cycloalkyl group;

[0215] (64) a process for preparation according to (60) or (63) whereinR¹¹ is a C₁-C₂₀ alkyl group, or a C₁-C₂₀ alkyl group substituted with anaryl group(s) or a heteroaryl group(s).

[0216] In the above formulae, an “aryl group” and an “aryl moiety” of anaryl group substituted with 1 to 3 substituents selected fromsubstituent group a; an aryl group substituted with 1 to 3 substituentsselected from substituent groups a and b; and an aryl group substitutedwith 1 to 5 substituents selected from substituent group a in thedefinition of X, R⁵, Ar and substituent group b each are, for example,an aromatic hydrocarbon having 6 to 10 carbons such as phenyl, indenyland naphthyl; preferably a phenyl or naphthyl group and most preferablya phenyl group.

[0217] In the above formulae, an “alkylene group” and an “alkylenemoiety” of a C₁-C₁₀ alkylene group substituted with 1 to 3 substituentsselected from substituent group a and b in the definition of Y each area straight or branched chain alkylene having 1 to 10 carbons such asmethylene, methylmethylene, ethylene, propylene, trimethylene,1-methylethylene, tetramethylene, 1-methyltrimethylene,2-methyltrimethylene, 3-methyltrimethylene, 1-methylpropylene,1,1-dimethylethylene, pentamethylene, 1-methyltetramethylene,2-methyltetramethylene, 3-methyltetramethylene, 4-methyltetramethylene,1,1-dimethytrimethylene, 2,2-dimethytrimethylene,3,3-dimethytrimethylene, hexamethylene, 1-methylpentamethylene,2-methylpentamethylene, 3-methylpentamethylene, 4-methylpentamethylene,5-methylpentamethylene, 1,1-dimlethyltetramethylene,2,2-dimethyltetramethylene, 3,3-dimethyltetramethylene,4,4-dimethyltetramethylene, heptamethylene, 1-methylhexamethylene,2-methylhexamethylene, 5-methylhexamethylene, 3-ethylpentamethylene,octamethylene, 2-methylheptamethylene, 5-methylheptamethylene,2-ethylhexamethylene, 2-ethyl-3-methylpentamethylene,3-ethyl-2-methylpentamethylene, nonamethylene, 2-methyloctamethylene,7-methyloctamethylene, 4-ethylheptamethylene,3-ethyl-2-methylhexamethylene, 2-ethyl-1-methylhexamethylene,decamethylene group; preferably a C₁-C₆ alkylene; more preferably aC₁-C₅ alkylene; still more preferably an ethylene, trimethylene ortetramethylene group; and most preferably an ethylene or trimethylenegroup.

[0218] In the above formulae, a “C₁-C₁₀ alkylene group which has anoxygen atom or a sulfur atom in said carbon chain or at the end of saidcarbon chain” and a “C₁-C₁₀ alkylene moiety which has an oxygen atom ora sulfur atom in said carbon chain or at the end of said carbon chain”of a C₁-C₁₀ alkylene group which is substituted with 1 to 3 substituentsselected from substituent groups a and b and has an oxygen atom or asulfur atom in said carbon chain or at the end of said carbon chain inthe definition of Y is a C₁-C₁₀ alkylene group indicated above which hasan oxygen atom or a sulfur atom in said carbon chain or at the end ofsaid carbon chain, for example, a group of formula —O—CH₂—, —O—(CH₂)₂—,—O—(CH₂)₃—, —O—(CH₂)₄—, —O—(CH₂)₅—, —O—(CH₂)₆—, —O—(CH₂)₇—, —O—(CH₂)₈—,—O—(CH₂)₉—, —O—(CH₂)₁₀—, —CH₂—O—CH₂—, —CH₂—O—(CH₂)₂—, —CH₂—O—(CH₂)₃—,—CH₂—O—(CH₂)₄—, —(CH₂)₂—O—CH₂—, —(CH₂)₂—O—(CH₂)₂—, —(CH₂)₂—O—(CH₂)—,—(CH₂)₂—O—(CH₂)₄—, —(CH₂)₃—O—CH₂—, —(CH₂)₃—O—(CH₂)₂—, —(CH₂)₃—O—(CH₂)₃—,—(CH₂)₄—O—CH₂—, —(CH₂)₄—O—(CH₂)₂—, —(CH₂)₅—O—CH₂—, —CH₂—O—, —(CH₂)₂—O—,—(CH₂)₃—O—, —(CH₂)₄—O—, —(CH₂)₅—O—, —(CH₂)₆—O—, —(CH₂)₇—O—, —(CH₂)₈—O—,—(CH₂)₉—O—, —(CH₂)₁₀—O—, —S—CH₂—, —S—(CH₂)₂—, —S—(CH₂)₃—, —S—(CH₂)₄—,—S—(CH₂)₅—, —S—(CH₂)₆—, —S—(CH₂)₇—, —S—(CH₂)₈—, —S—(CH₂)₉—, —S—(CH₂)₁₀—,—CH₂—S—CH₂—, —CH₂—S—(CH₂)₂—, —CH₂—S—(CH₂)₃—, —CH₂—S—(CH₂)₄—,—(CH₂)₂—S—CH₂—, —(CH₂)₂—S—(CH₂)₂—, —(CH₂)₂—S—(CH₂)₃—, —(CH₂)₂—S—(CH₂)₄—,—(CH₂)₃—S—CH₂—, —(CH₂)₃—S—(CH₂)₂—, —(CH₂)₃—S—(CH₂)₃—, —(CH₂)₄—S—CH₂—,—(CH₂)₄—S—(CH₂)₂—, —(CH₂)₅—S—CH₂—, —CH₂—S—(CH₂)₂—S, —(CH₂)₃—S—,—(CH₂)₄—S—, —(CH₂)₅—S—, —(CH₂)₆—S—, —(CH₂)₇—S—, —(CH₂)₈—S—, —(CH₂)₉—S—,—(CH₂)₁₀—S—; preferably a C₁-C₆ alkylene group which has an oxygen atomin said carbon chain or at the end of carbon chain; more preferably—O—CH₂—, —O—(CH₂)₂—, —O—(CH₂)₃—, —CH₂—O—, —(CH₂)₂—O—, or —(CH₂)₃—O—; andmost preferably —CH₂—O—, —O—(CH₂)₂—, or —(CH₂)₂—O—.

[0219] In the above formulae the “cycloalkyl groups” in substituentgroups b and the “cycloalkyl moieties” of the cycloalkyl groupsubstituted with 1 to 3 substituents selected from substituent group aand the cycloalkyl group substituted with 1 to 3 substituents selectedfrom substituent groups a and b in the definitions of R^(4a), R⁵ andR¹¹, each comprise a saturated carbon ring having 3 to 10 carbons, whichis optionally fused with a cyclic group(s) such as a benzene ring, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,norbornyl, adamantyl and indanyl. A preferred cycloalkyl group in thedefinition of R⁵ and substituent group b is a C₅-C₆ cycloalkyl group andthe most preferred one is a cyclohexyl group. On the other hand apreferred cycloalkyl group in the definition of R^(4a) and R¹¹ is aC₅-C₁₀ cycloalkyl group.

[0220] In the above formulae the “heteroaryl group” and the “heteroarylmoiety” of the heteroaryl group substituted with 1 to 5 substituentsselected from substituent group a in the definition of Ar each comprisea 5- to 7-membered heterocyclic group having 1 to 3 of a sulfur atom(s),an oxygen atom(s) and/or a nitrogen atom(s), for example, furyl,thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl,tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl andpyrazinyl.

[0221] In addition, the heteroaryl group indicated above optionally maybe fused with a cyclic group. Examples of such a group include, forexample, benzothienyl, isobenzofuranyl, chromenyl, xanthenyl,phenoxathiinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl,quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthylizinyl,quinoxalinyl, quinazolinyl, carbazolyl, carbolinyl, acridinyl andisoindolinyl. Preferred heteroaryl groups are a furyl, thienyl orbenzothienyl group and the most preferred heteroaryl group is a thienylor a benzothienyl group.

[0222] In the above formulae the “heterocyclic groups” in the definitionof R⁵ and substituent group b and the “heterocyclic moiety” of theheterocyclic group substituted with 1 to 3 substituents selected fromsubstituent group a and the heterocyclic group substituted with 1 to 3substituents selected from substituent groups a and b each represent a5- to 7 membered heterocyclic group having 1 to 3 of a sulfur atom(s),an oxygen atom and/or a nitrogen atom, and examples of such heterocyclicgroups include the heteroaryl groups indicated above, and heterocycliccompounds corresponding to partially or completely hydrogenatedheteroaryl groups indicated above such as tetrahydropyranyl,morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolyl, imidazolidinyl,pyrazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,thiazolidinyl and pyrazolidinyl. Preferred heterocyclic groups are 5- or6-membered heteroaryl groups and the most preferred heteocyclic group isa morpholinyl, thiomorpholinyl or piperidinyl group.

[0223] In the above formulae the “halogen atom” in the definition ofsubstituent group a is a fluorine, chlorine, bromine or iodine atom;preferably a fluorine atom or chlorine atom and most preferably afluorine atom.

[0224] In the above formulae the “lower alkyl groups” in the definitionof R⁴ and substituent group a each represent, for example, a straight orbranched chain alkyl group having 1 to 6 carbons such as a methyl,ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl,isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl,4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl,3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl or2-ethylbutyl group; preferably a C₁-C₄ alkyl group; more preferably aC₁-C₂ alkyl group and most preferably a methyl group.

[0225] In the above formulae the “halogenated lower alkyl group” in thedefinition of substituent group a represents the lower alkyl group,which is described hereinbefore which is substituted with a haologenatom(s), for example, a halogenated C₁-C₆ alkyl group such as atrifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl,dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl,2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl,4-fluorobutyl, 6-iodohexyl or 2,2-dibromoethyl group; preferably ahalogenated C₁-C₄ alkyl group; more preferably a halogenated C₁-C₂ alkylgroup; and most preferably a trifluoromethyl group.

[0226] In the above formulae the “lower alkoxy group” in the definitionof substituent group a represents an oxygen atom which is attached tothe lower alkyl group described hereinbefore, for example, a straight orbranched chain alkoxy group having 1 to 6 carbons such as a methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy,pentoxy, isopentoxy, 2-methylbutoxy, 1-ethylpropoxy, 2-ethylpropoxy,neopentoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy,3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy,1,2-dimethylbutoxy, 1,3-dimethylbutoxy or 2,3-dimethylbutoxy group;preferably a C₁-C₄ alkoxy group; more preferably a C₁-C₂ alkoxy group;and most preferably a methoxy group.

[0227] In the above formulae the “lower alkylthio group” in thedefinition of substituent group a represents a sulfur atom which isattached to a lower alkyl group described hereinbefore, for example, analkylthio group having 1 to 6 carbons such as a methylthio, ethylthio,propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio,t-butylthio, pentylthio, isopentylthio, 2-methylbutylthio,neopentylthio, hexylthio, 4-methylpentylthio, 3-methylpentylthio,2-methylpentylthio, 3,3-dimethylbutylthio, 2,2-dimethylbutylthio,1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio or2,3-dimethylbutylthio group; preferably a C₁-C₄ alkylthio group; morepreferably a C₁-C₂ alkylthio group; and most preferably a methylthiogroup.

[0228] In the above formulae the “lower alkoxycarbonyl group” in thedefinition of substituent group a represents a carbonyl group which isattached to the lower alkoxy group described hereinbefore, for example,a straight or branched chain alkoxycarbonyl group having 1 to 6 carbonssuch as a methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl,t-butoxycarbonyl, pentoxycarbonyl, isopentoxycarbonyl,2-methylbutoxycarbonyl, neopentoxycarbonyl, hexyloxycarbonyl,4-methylpentoxycarbonyl, 3-methylpentoxycarbonyl,2-methylpentoxycarbonyl, 3,3-dimethylbutoxycarbonyl,2,2-dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl,1,2-dimethylbutoxycarbonyl, 1,3-dimethylbutoxycarbonyl or2,3-dimethylbutoxycarbonyl group; preferably a C₁-C₄ alkoxycarbonylgroup; more preferably a C₁-C₂ alkoxycarbonyl group; and most preferablya methoxycarbonyl group.

[0229] In the above formulae the “lower aliphatic acyl group” in thedefinition of substituent group a represents a carbonyl group which isattached to a hydrogen atom or a saturated or unsaturated chainhydrocarbon, for example, a straight or branched chain lower aliphaticacyl group having 1 to 7 carbons such as a formyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, acryloyl,methacryloyl or crotonoyl group; preferably a C₁-C₄ lower aliphatic acylgroup; more preferably an acetyl or propionyl group; and most preferablyan acetyl group.

[0230] In the above formulae the “mono lower alkylamino group” in thedefinition of substituent group a represents an amino group which isattached to one alkyl group described hereinbefore, for example, a monoC₁-C₆ alkylamino group such as a methylamino, ethylamino, propylamino,isopropylamino, butylamino, isobutylamino, s-butylamino, t-butylamino,pentylamino, isopentylamino, 2-methylbutylamino, neopentylamino,1-ethylpropylamino, hexylamino, isohexylamino, 4-methylpentylamino,3-methylpentylamino, 2-methylpentylamino, 1-methyl-pentylamino,3,3-dimethylbutylamino, 2,2-dimethylbutylamino, 1,1-dimethylbutylamino,1,2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,3-dimethylbutylaminoor 2-ethylbutylamino group; preferably a C₁-C₄ alkylamino group; morepreferably a C₁-C₂ alkyl amino group; and most preferably a methylaminogroup.

[0231] In the above formulae the “di lower alkylamino group” in thedefinition of substituent group a represents an amino group which isattached to two alkyl groups described hereinbefore, for example, a diC₁-C₆ alkylamino group such as a dimethylamino, diethylamino,N-ethyl-N-methylamino, dipropylamino, dibutylamino, dipentylamino ordihexylamino group; preferably a di C₁-C₄ alkylamino group; morepreferably a di C₁-C₂ alkyl amino group; and most preferably adimethylamino group.

[0232] In the above formulae the “lower aliphatic acylamino group” inthe definition of substituent group a represents, for example, astraight or branched chain aliphatic acylamino group having 1 to 7carbons such as a formylamino, acetylamino, propionylamino,butyrylamino, isobutyrylamino, valerylamino, isovalerylamino,pivaloylamino, hexanoylamino, acryloylamino, methacryloylamino orcrotonoylamino group; preferably an acetylamino or propionylamino group;and most preferably an acetylamino group.

[0233] In the above formulae the “amino protecting groups” in thedefinition of R¹ and R² each represent an amino protecting group knownto those skilled in organic synthesis, for example:

[0234] the lower alkyl group described hereinbefore; an aliphatic acylgroup, for example, the lower aliphatic acyl group describedhereinbefore, a halogenated lower aliphatic acyl group such aschloroacetyl, dichloroacetyl, trichloroacetyl or trifluoroacetyl or alower aliphatic acyl group substituted with a lower alkoxy group such asmethoxyacetyl; an aromatic acyl group, for example, an aromatic acylgroup such as benzoyl, 1-indancarbonyl, 2-indancarbonyl or 1- or2-naphthoyl, or an aromatic acyl group substituted with 1 to 3substituents selected from substituent group a such as 4-chlorobenzoyl,4-fluorobenzoyl, 2,4,6-trimethylbenzoyl, 4-toluoyl, 4-anisoyl,4-nitrobenzoyl, 2-nitrobenzoyl, 2-(methoxycarbonyl)benzoyl or4-phenylbenzoyl; an alkoxycarbonyl group, for example, the loweralkoxycarbonyl described hereinbefore or a lower alkoxycarbonyl groupsubstituted with a halogen atom(s) or a tri lower alkylsilyl group(s)such as 2,2,2-trichloroethoxycarbonyl or2-trimethylsilyl-ethoxycarbonyl; an alkenyloxycarbonyl group such asvinyloxycarbonyl or allyloxycarbonyl; an aralkyloxycarbonyl group, forexample, an aralkyloxycarbonyl group such as a benzyloxycarbonyl groupor an aralkyloxycarbonyl group substituted with 1 to 3 substituentsselected from substituent group a such as 4-methoxybenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl or4-nitrobenzyloxycarbonyl; a silyl group, for example, a lower alkylsilylgroup such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl,t-butyldimethylsilyl, methyldiisopropylsilyl, methyl-di-t-butylsilyl ortriisopropylsilyl, a silyl group tri substituted with an aryl group(s)or with an aryl(s) and a lower alkyl group(s) such asdiphenylmethylsilyl or diphenylbutylsilyl, diphenylisopropylsilyl,phenyldiisopropylsilyl; an aralkyl group, for example a lower alkylgroup substituted with 1 to 3 aryl groups such as benzyl, phenethyl,3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl,triphenylmethyl, α-naphthyldiphenylmethyl or 9-anthrylmethyl or a loweralkyl group substituted with 1 to 3 substituted aryl groups wherein saidaryl group is substituted with lower alkyl, lower alkoxy, nitro, halo orcyano, such as 4-methylbenzyl, 2,4,6-trimethylbenzyl,3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxy-phenyldiphenylmethyl,2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl,4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis(2-nitrophenyl)methyl orpiperonyl; and a substituted methylene group which forms a Schiff basesuch as N,N-dimethylaminomethylene, benzylidene, 4-methoxybenzylidene,4-nitrobenzylidene, salicylidene, 5-chlorosalicylidene,diphenylmethylene or (5-chloro-2-hydroxyphenyl)phenylmethylene;

[0235] preferably a lower alkoxycarbonyl group, an aralkyloxycarbonylgroup or an aralkyloxycarbonyl group substituted with 1 to 3substituents selected from substituent group a.

[0236] The “hydroxy protecting group” in the definition R³ and R^(3a)represents a general protecting group which can be deprotected by achemical process such as hydrogenolysis, hydrolysis, electrolysis,photolysis and a protecting group which can be deprotected by abiological process such as hydrolysis in vivo.

[0237] Examples of general protecting groups includes the lower alkylgroups described hereinbefore; the aliphatic acyl groups describedhereinbefore; the aromatic acyl groups described hereinbefore; atetrahydropyranyl or tetrahydrothiopyranyl group such astetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl or 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl or4-methoxytetrahydrothiopyran-4-yl; a tetrahydrofuranyl ortetrahydrothiofuranyl group such as tetrahydrofuran-2-yl ortetrahydrothiofuran-2-yl; the silyl groups described hereinbefore; analkoxymethyl group, for example, a lower alkoxylated lower alkoxymethylgroup such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl,propoxymethyl, isopropoxymethyl, butoxymethyl or t-butoxymethyl; a loweralkoxylated alkoxymethyl group such as 2-methoxyethoxymethyl or ahalogenated lower alkoxymethyl group such as 2,2,2-trichloroethoxymethylor bis(2-chloroethoxy)methyl; a substituted ethyl group, for example alower alkoxylated ethyl group such as 1-ethoxyethyl or1-(isopropoxy)ethyl or a halogenated ethyl group such as2,2,2-trichloroethyl; the aralkyl groups described hereinbefore; thealkoxycarbonyl groups described hereinbefore; and the alkenyloxycarbonylgroup described hereinbefore; the aralkyloxycarbonyl group describedhereinbefore.

[0238] On the other hand examples of a protecting group which can bedeprotected by a biological process such as hydrolysis in vivo, includean acyloxyalkyl group such as ethylcarbonyloxymethyl, pivaloyloxymethyl,dimethylaminoacetyloxymethyl or 1-acetoxyethyl; a1-(alkoxycarbonyloxy)alkyl group such as 1-(methoxycarbonyloxy)ethyl,1-(ethoxycarbonyloxy)ethyl, ethoxycarbonyloxymethyl,1-(isopropoxycarbonyloxy)ethyl, 1-(t-butoxycarbonyloxy)ethyl,1-(ethoxycarbonyloxy)propyl or 1-(cyclohexyloxycarbonyloxy)ethyl; aphthalidyl group; a carbonyloxyalkyl group, for example, anoxodioxolenylmethyl group such as 4-methyloxodioxolenylmethyl or4-phenyloxodioxolenylmethyl; the aliphatic acyl groups describedhereinbefore; the aromatic acyl groups described hereinbefore; aresidual group of a half ester of succinic acid; a residual group of anester of phosphoric acid; a residual group of an ester formation of anamino acid; a carbamoyl group; an alkylidene group such as benzylidene;an alkoxyethylidene group such as methoxyethylidene or ethoxyethylidene;a protecting group of two hydroxyl groups such as oxomethylene oroxoethylene; and a carbonyloxyalkyloxycarbonyl group such aspivaloyloxymethyloxycarbonyl.

[0239] Whether a compound of formula (I) has such a group can bedetermined as follows. The derivative under investigation isintravenously administered to a test animal such as a rat or mouse andthe body fluids of the test animal are thereafter studied. If the parentcompound of said derivative or a pharmaceutically acceptable salt of theparent compound is detected in said body fluid, said derivative underinvestigation is judged to have a protecting group which can bedeprotected by biological process. Examples of such a hydroxy protectinggroup are preferably a lower alkyl group, a lower aliphatic acyl group,an aromatic acyl group or an aromatic acyl group substituted with 1 to 3substituents selected from substituent group a.

[0240] In the above formulae typical examples of the “cycloalkyl groupsubstituted with 1 to 3 substituents selected from substituent groups aand b” in the definition of R⁵ are, for example, a 2-fluorocyclopropyl,2-chlorocyclopropyl, 2- or 3-fluorocyclopentyl, 2- or3-chlorocyclopentyl, 2-, 3- or 4-fluorocyclohexyl, 2-, 3- or4-chlorocyclohexyl, 2-, 3- or 4-bromocyclohexyl, 2-, 3- or4-iodocyclohexyl, 2-methylcyclopropyl, 2-ethylcyclopropyl, 2- or3-methylcyclopentyl, 2- or 3-ethylcyclopentyl, 2-, 3- or4-methylcyclohexyl, 2-, 3- or 4-ethylcyclohexyl,2-trifluoromethylcyclopropyl, 2- or 3-trifluoromethylcyclobutyl, 2- or3-trifluoromethylcyclopentyl, 2-, 3- or 4-trifluoromethylcyclohexyl,2-methoxycyclopropyl, 2- or 3-methoxycyclobutyl, 2- or3-methoxycyclopentyl, 2-, 3- or 4-methoxycyclohexyl, 2-, 3- or4-ethoxycyclohexyl, 2-, 3- or 4-propoxycyclohexyl, 2-, 3- or4-isopropoxycyclohexyl, 2-, 3- or 4-(1-ethylpropoxy)cyclohexyl, 2-, 3-or 4-(2-ethylpropoxy)cyclohexyl, 2-carboxycyclopropyl, 2- or3-carboxycyclopentyl, 2-, 3- or 4-carboxycyclohexyl,2-methoxycarbonylcyclopropyl, 2- or 3-methoxycarbonylcyclopentyl, 2-, 3-or 4-methoxycarbonylcyclohexyl, 2-hydroxycyclopropyl, 2- or3-hydroxycyclopentyl, 2-, 3- or 4-hydroxycyclohexyl,2-formylcyclopropyl, 2- or 3-formylcyclopentyl, 2-, 3- or4-formylcyclohexyl, 2-acetylcyclopropyl, 2- or 3-acetylcyclopentyl, 2-,3- or 4-acetylcyclohexyl, 2-aminocyclopropyl, 2- or 3-aminocyclopentyl,2-, 3- or 4-aminocyclohexyl, 2-methylaminocyclopropyl, 2- or3-methylaminocyclobutyl, 2- or 3-methylaminocyclopentyl, 2-, 3- or4-methylaminocyclohexyl, 2-dimethylaminocyclopropyl, 2- or3-dimethylaminocyclobutyl, 2- or 3-dimethylaminocyclopentyl, 2-, 3- or4-dimethylaminocyclohexyl, 2-cyanocyclopropyl, 2- or 3-cyanocyclopentyl,2-, 3- or 4-cyanocyclohexyl, 2- or 3-cyclohexylcyclopentyl, 2-, 3- or4-cyclohexylcyclohexyl, 2-phenylcyclopropyl, 2- or 3-phenylcyclopentyl,2-, 3- or 4-phenylcyclohexyl, 3,4-difluorocyclohexyl,3,4-dichlorocyclohexyl, 2,3-dimethoxycyclohexyl,3,4-dimethoxycyclohexyl, 3,5-dimethoxycyclohexyl, or3,4,5-trimethoxycyclohexyl group; preferably a cycloalkyl groupsubstituted with 1 to 3 substituents (said substituent is selected fromthe group consisting of a halogen atom, a lower alkyl group, ahalogenated lower alkyl group, a lower alkoxy group, a lower alkylthiogroup, and a lower aliphatic acyl group); more preferably a cycloalkylgroup substituted with 1 to 3 substituents (said substituent is selectedfrom the group consisting of a halogen atom, a lower alkyl group, ahalogenated lower alkyl group, a lower alkoxy group, and a loweraliphatic acyl group); still more preferably a cyclohexyl groupsubstituted with 1 to 3 substituents (said substituent is selected fromthe group consisting of a halogen atom, a lower alkyl group, ahalogenated lower alkyl group, a lower alkoxy group, and a loweraliphatic acyl group); most preferably a cyclohexyl group substitutedwith 1 to 3 substituents (said substituent is selected from the groupconsisting of a fluorine atom, a chlorine atom, and methyl,trifluoromethyl, methoxy and acetyl groups).

[0241] In the above formulae typical examples of the “aryl groupsubstituted with 1 to 3 substituents selected from substituent groups aand b” in the definition of R⁵ are, for example, a 2-, 3- or4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 2-, 3- or 4-bromophenyl, 2-,3- or 4-iodophenyl, 2-, 3- or 4-methylphenyl, 2-, 3- or 4-ethylphenyl,2-, 3-, 4-propylphenyl, 2-, 3- or 4-butylphenyl, 2-, 3- or4-pentylphenyl, 2-, 3- or 4-trifluoromethylpheynyl, 2-, 3- or4-methoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 2-, 3- or 4-propoxyphenyl,2-, 3- or 4-isopropoxyphenyl, 2-, 3- or 4-butoxyphenyl, 2-, 3- or4-(1-ethylpropoxy)phenyl, 2-, 3- or 4-(2-ethylpropoxy)phenyl, 2-, 3- or4-methylthiophenyl, 2-, 3- or 4-ethylthiophenyl, 2-, 3- or4-carboxyphenyl, 2-, 3- or 4-methoxycarbonylphenyl, 2-, 3- or4-ethoxycarbonylphenyl, 2-, 3- or 4-hydroxyphenyl, 2-, 3- or4-formylphenyl, 2-, 3- or 4-acetylphenyl, 2-, 3- or 4-aminophenyl, 2-,3-, or 4-methylaminophenyl, 2-, 3- or 4-dimethylaminophenyl, 2-, 3- or4-cyanophenyl, 2-, 3- or 4-cyclopentylphenyl, 2-, 3- or4-cyclohexylphenyl, 2-, 3- or 4-biphenyl, 2,4-difluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 2,4-dichlorophenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,4-dibromophenyl,2,3-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl,2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl,3,4,5-trimethoxyphenyl, 3-fluoro-4-methoxyphenyl,4-methyl-2-methoxyphenyl, 6-fluoro-4-methyl-2-methoxyphenyl,5-fluoroinden-3-yl, 5-fluoroinden-3-yl, 5-methylinden-3-yl,5-methoxyinden-3-yl, 5-fluoroinden-2-yl, 5-chloroinden-2-yl,5-methylinden-2-yl, 5-methoxyinden-2-yl, 5-hydroxyinden-3-yl,5-nitroinden-3-yl, 5-cyclohexylinden-3-yl, 5-phenylinden-3-yl,5-phenoxyinden-3-yl, 5-benzyloxyinden-3-yl, 5-phenylthioinden-3-yl,5-hydroxyinden-2-yl, 5-nitroinden-2-yl, 5-cyclohexylinden-2-yl,5-phenylinden-2-yl, 5-fluoronaphthalen-2-yl, 5-methylnaphthalen-2-yl,5-methoxynaphthalen-2-yl, 5-fluoronaphthalen-1-yl,5-methylnaphthalen-1-yl, 5-methoxynaphthalen-1-yl,5-hydroxynaphthalen-2-yl, 5-nitronaphthalen-2-yl,5-cyclohexylnaphthalen-2-yl, 5-phenylnaphthalen-2-yl,5-phenoxynaphthalen-2-yl, 5-benzyloxynaphthalen-2-yl,5-phenylthionaphthalen-2-yl, 5-hydroxynaphthalen-l -yl,5-nitronaphthalen-1-yl, 5-cyclohexylnaphthalen-1-yl or5-phenylnaphthalen-1-yl group; preferably an aryl group substituted with1 to 3 substituents (said substituent is selected from the groupconsisting of a halogen atom, a lower alkyl group, a halogenated loweralkyl group, a lower alkoxy group, a lower alkylthio group and a loweraliphatic acyl group); more preferably an aryl group substituted with 1to 3 substituents (said substituent is selected from the groupconsisting of a halogen atom, a lower alkyl group, a halogenated loweralkyl group, a lower alkoxy group, and a lower aliphatic acyl group);more preferably a phenyl group substituted with 1 to 3 substituents(said substituent is selected from the group consisting of a halogenatom, a lower alkyl group, a halogenated lower alkyl group, a loweralkoxy group, and a lower aliphatic acyl group); still more preferably aphenyl group substituted with 1 to 3 substituents (said substituent isselected from the group consisting of a fluorine atom, a chlorine atomand methyl, trifluoromethyl, methoxy and acetyl groups); and mostpreferably a 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl,3,5-dichlorophenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl,3,5-dimethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl,3,4-ditrifluoromethylphenyl, 3,5-ditrifluoromethylphenyl,3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl,3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3-acetylphenyl, or4-acetylphenyl group.

[0242] In the above formulae typical examples of the “heterocyclic groupsubstituted with 1 to 3 substituents selected from substituent groups aand b” in the definition of R⁵ are, for example, a 3-, 4- or5-methylfuran-2-yl, 2-, 4- or 5-methylfuran-3-yl, 3-, 4- or5-fluorothiophen-2yl, 2-, 4- or 5-fluorofuran-3-yl, 3-, 4- or5-bromothiophen-2-yl, 2-, 4- or 5-bromofuran-3-yl, 3-, 4- or5-methylthiophen-2-yl, 2-, 4- or 5-methylthiophen-3-yl, 3-, 4- or5-ethylthiophen-2yl, 2-, 4- or 5-ethylthiophen-3-yl, 3-, 4- or5-methoxythiophen-2-yl, 2-, 4- or 5-methoxythiophen-3-yl, 3- or4-methylthiazol-5-yl, 3-, 4- or 5-fluorobenzothiophen-2-yl, 3-, 4- or5-bromobenzothiophen-2-yl, 3-, 4- or 5-methylbenzothiophen-2-yl, 3-, 4-or 5-methoxybenzothiophen-2-yl, 2-, 4- or 5-fluorobenzothiophen-3-yl,2-, 4- or 5-bromobenzothiophen-3-yl, 2-, 4- or5methylbenzothiophen-3-yl, 2-, 4- or 5-methoxybenzothiophen-3-yl, 4-,5-, 6- or 7-methylbenzothiophen-2-yl, 3-, 4- or 5-hydroxyfuran-2-yl, 2-,4- or 5-hydroxyfuran-3-yl, 3-, 4- or 5-hydroxythiophen-2-yl, 3-, 4- or5-nitrothiophen-2-yl, 3-, 4- or 5-phenylthiophen-2-yl, 2-, 4- or5-hydroxythiophen-3-yl, 2-, 4- or 5-cyanothiophen-3-yl, 1-, 2- or3-hydroxypyridin-4-yl, 1-, 2- or 3-cyanopyridin-4-yl or 1-, 2- or3-phenylpyridin-4-yl group; and preferably a 3-, 4- or5-fluorothiophen-2-yl or 3-, 4-, or 5-fluorofuran-3-yl group.

[0243] In the above formulae examples of the “C₁-C₂₀ alkyl groups” inthe definition of R^(4a) and R¹¹ are, for example, a straight orbranched chain alkyl group having 1 to 20 carbons such as the loweralkyl groups described hereinbefore, heptyl, 1-methylhexyl,2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,1-propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl,2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl,6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, nonyl,3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl,1-propylhexyl, 2-ethylheptyl, 6,6-dimethylheptyl, decyl, 1-methylnonyl,3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl,7,7-dimethyloctyl, undecyl, 4,8-dimethylnonyl, dodecyl, tridecyl,tetradecyl, pentadecyl, 3,7,11-trimethyldodecyl, hexadecyl,4,8,12-trimethyltridecyl, 1-methylpentadecyl, 14-methylpentadecyl,13,13-dimethyltetradecyl, heptadecyl, 15-methylhexadecyl, octadecyl,1-methylheptadecyl, nonadecyl, icosyl and 3,7,11,15-tetramethylhexadecylgroup; preferably a C₁-C₁₀ alkyl group; more preferably a C₁-C₆ alkylgroup; and most preferably a methyl or ethyl group.

[0244] In the above formulae the “C₂-C₂₀ alkyl group interrupted with ahetero atom(s)” in the definition of R^(4a) and R¹¹ represents theC₂-C₂₀ alkyl groups which are described hereinbefore and which areinterrupted with 1 or 2 of the same or different heteroatoms such as asulfur atom, an oxygen atom or a nitrogen atom. Examples of such groupinclude an alkyl group, which has 2 to 20 carbons and is interruptedwith one or two sulfur atoms, such as methylthiomethyl,1-methylthioethyl, 2-methylthioethyl, ethylthiomethyl,1-methylthiopropyl, 2-methylthiopropyl, 3-methylthiopropyl,2-ethylthioethyl, 2-methyl-2-methylthioethyl, 1-methylthiobutyl,2-methylthiobutyl, 3-methylthiobutyl, 2-ethylthiopropyl,3-methyl-3-methylthiopropyl, 4-methylthiopentyl, 3-methylthiopentyl,2-methylthiopentyl, 1-methylthiopentyl, 3,3-dimethylthiobutyl,2,2-dimethylthiobutyl, 1,1-dimethylthiobutyl,1-methyl-2-methylthiobutyl, 1,3-dimethylthiobutyl,2,3-dimethylthiobutyl, 2-ethylthiobutyl, 1-methylthiohexyl,2-methylthiohexyl, 3-methylthiohexyl, 4-methylthiohexyl,5-methylthiohexyl, 1-propylthiobutyl, 4-methyl-4-methylthiopentyl,1-methylthioheptyl, 2-methylthioheptyl, 3-methylthioheptyl,4-methylthioheptyl, 5-methylthioheptyl, 6-methylthioheptyl,1-propylthiopentyl, 2-ethylthiohexyl, 5-methyl-5-methylthiohexyl,3-methylthiooctyl, 4-methylthiooctyl, 5-methylthiooctyl,6-methylthiooctyl, 1-propylthiohexyl, 2-ethylthioheptyl,6-methyl-6-methylthioheptyl, 1-methylthiononyl, 3-methylthiononyl,8-methylthiononyl, 3-ethylthiooctyl, 3-methyl-7-methylthiooctyl,7,7-dimethylthiooctyl, 4-methyl-8-methythiononyl,3,7-dimethyl-11-methylthiododecyl, 4,8-dimethyl-12-methylthiotridecyl,1-methylthiopentadecyl, 14-methylthiopentadecyl,13-methyl-13-methylthiotetradecyl, 15-methylthiohexadecyl,1-methylthioheptadecyl, and 3,7,11-trimethyl-15-methylthiohexadecyl; analkyl group, which has 2 to 20 carbons and is interrupted with one ortwo oxygen atoms, such as methyloxymethyl, 1-methyloxyethyl,2-methyloxyethyl, ethyloxymethyl, 1-methyloxypropyl, 2-methyloxypropyl,3-methyloxypropyl, 2-ethyloxyethyl, 2-methyl-2-methyloxyethyl,1-methyloxybutyl, 2-methyloxybutyl, 3-methyloxybutyl, 2-ethyloxypropyl,3-methyl-3-methyloxypropyl, 4-methyloxypentyl, 3-methyloxypentyl,2-methyloxypentyl, 1-methyloxypentyl, 3,3-dimethyloxybutyl,2,2-dimethyloxybutyl, 1,1-dimethyloxybutyl, 1-methyl-2-methyloxybutyl,1,3-dimethyloxybutyl, 2,3-dimethyloxybutyl, 2-ethyloxybutyl,1-methyloxyhexyl, 2-methyloxyhexyl, 3-methyloxyhexyl, 4-methyloxyhexyl,5-methyloxyhexyl, 1-propyloxybutyl, 4-methyl-4-methyloxypentyl,1-methyloxyheptyl, 2-methyloxyheptyl, 3-methyloxyheptyl,4-methyloxyheptyl, 5-methyloxyheptyl, 6-methyloxyheptyl,1-propyloxypentyl, 2-ethyloxyhexyl, 5-methyl-5-methyloxyhexyl,3-methyloxyoctyl, 4-methyloxyoctyl, 5-methyloxyoctyl, 6-methyloxyoctyl,1-propyloxyhexyl, 2-ethyloxyheptyl, 6-methyl-6-methyloxyheptyl,1-methyloxynonyl, 3-methyloxynonyl, 8-methyloxynonyl, 3-ethyloxyoctyl,3-methyl-7-methyloxyoctyl, 7,7-dimethyloxyoctyl,4-methyl-8-methyoxynonyl, 3,7-dimethyl-11-methyloxydodecyl,4,8-dimethyl-12-methyloxytridecyl, 1-methyloxypentadecyl,14-methyloxypentadecyl, 13-methyl-13-methyloxytetradecyl,15-methyloxyhexadecyl, 1-methyloxyheptadecyl, and3,7,11-trimethyl-15-methyloxyhexadecyl; an alkyl group, which has 1 to20 carbons and is interrupted with one or two nitrogen atoms, such asN-methylaminomethyl, 1-(N-methylamino)ethyl, 2-(N-methylamio)ethyl,N-ethylaminomethyl, 1-(N-methylamino)propyl, 2-(N-methylamino)propyl,3-(N-methylamino)propyl, 2-(N-ethylamino)ethyl,2-(N,N-dimethylamino)ethyl, l-(N-methylamino)butyl,2-(N-methylamino)butyl, 3-(N-methylamino)butyl, 2-(N-ethylamino)propyl,3-(N,N-dimethylamino)propyl, 4-(N-methylamino)pentyl,3-(N-methylamino)pentyl, 2-(N-methylamino)pentyl,1-(N-methylamino)pentyl, 3-(N,N-dimethylamino)butyl,2-(N,N-dimethylamino)butyl, 1-(N,N-dimethylamino)butyl,1-methyl-2-(N-methylamino)butyl, 1,3-di(N-methylamino)butyl,2,3-di(N-methylamino)butyl, 2-(N-ethylamino)butyl,1-(N-methylamino)hexyl, 2-(N-methylamino)hexyl, 3-(N-methylamino)hexyl,4-(N-methylamino)hexyl, 5-(N-methylamino)hexyl, 1-(N-propylamino)butyl,4-methyl-4-(N-methylamino)pentyl, 1-(N-methylamino)heptyl,2-(N-methylamino)heptyl, 3-(N-methylamino)heptyl,4-(N-methylamino)heptyl, 5-(N-methylamino)heptyl,6-(N-methylamino)heptyl, 1-(N-propylamino)pentyl, 2-(N-ethylamino)hexyl,5-methyl-5-(N-methylamino)hexyl, 3-(N-methylamino)octyl,4-(N-methylamino)octyl, 5-(N-methylamino)octyl, 6-(N-methylamino)octyl,1-(N-propylamino)hexyl, 2-(N-ethylamino)heptyl,6-methyl-6-(N-methylamino)heptyl, 1-(N-methylamino)nonyl,3-(N-methylamino)nonyl, 8-(N-methylamino)nonyl, 3-(N-ethylamino)octyl,3-methyl-7-(N-methylamino)octyl, 7,7-di(N-methylamino)octyl,4-methyl-8-(N-methylamino)nonyl, 3,7-dimethyl-11-(N-methylamino)dodecyl,4,8-dimethyl-12-(N-methylamino)dodecyl, 1-(N-methylamino)pentadecyl,14-(N-methylamino)pentadecyl, 13-methyl-13-(N-methylamino)tetradecyl,15-(N-methylamino)hexadecyl, 1-(N-methylamino)heptadecyl, and3,7,11-trimethyl-15-(N-methylamino)hexadecyl; and preferably a C₂-C₁₀alkyl group interrupted with a heteroatom(s).

[0245] In the above formulae the “C₁-C₂₀ alkyl group substituted with anaryl group(s) or a heteroaryl group(s)” in the definition of R^(4a) andR¹¹ represents the C₁-C₂₀ alkyl groups described hereinbeforesubstituted with 1 to 3 of the same or different aryl groups describedhereinbefore or the same or different heteroaryl groups describedhereinbefore.

[0246] In the above formulae the “C₂-C₂₀ alkynyl group” in thedefinition of R^(4a) and R¹¹ comprises, for example, a straight orbranched chain alkynyl group having 2 to 20 carbons such as an ethynyl,2-propynyl, 1-methyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl,1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl,1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 3-pentynyl,1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl,1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl,4-hexynyl, 5-hexynyl, heptynyl, 1-methylhexynyl, 2-methylhexynyl,3-methylhexynyl, 4-methylhexynyl, 5-methylhexynyl, 1-propylbutynyl,4,4-dimethylpentynyl, octynyl, 1-methylheptynyl, 2-methylheptynyl,3-methylheptynyl, 4-methylheptynyl, 5-methylheptynyl, 6-methylheptynyl,1-propylpentynyl, 2-ethylhexynyl, 5,5-dimethylhexynyl, nonynyl,3-methyloctynyl, 4-methyloctynyl, 5-methyloctynyl, 6-methyloctynyl,1-propylhexynyl, 2-ethylheptynyl, 6,6-dimethylheptynyl, decynyl,1-methylnonynyl, 3-methylnonynyl, 8-methylnonynyl, 3-ethyloctynyl,3,7-dimethyloctynyl, 7,7-dimethyloctynyl, undecynyl,4,8-dimethylnonynyl, dodecynyl, tridecynyl, tetradecynyl, pentadecynyl,3,7,11-trimethyldodecynyl, hexadecynyl, 4,8,12-trimethyltridecynyl,1-methylpentadecynyl, 14-methylpentadecynyl, 13,13-dimethyltetradecynyl,heptadecynyl, 15-methylhexadecynyl, octadecynyl, 1-methylheptadecynyl,nonadecynyl, icosynyl or 3,7,11,15-tetramethylhexadecynyl group;preferably a C₂-C₁₀ alkynyl group.

[0247] In the above formulae the “C₃-C₂₀ alkynyl group interrupted witha hetero atom(s)” in the definition of R^(4a) and R¹¹ represents theC₃-C₂₀ alkynyl groups which are described hereinbefore and which areinterrupted with 1 or 2 of the same or different heteroatoms such as asulfur atom, an oxygen atom or a nitrogen atom. Examples of such groupsinclude an alkynyl group which has 3 to 20 carbons and is interruptedwith one or two sulfur atoms, such as 1-methylthioethynyl,2-methylthioethynyl, 1-methylthiopropynyl, 2-methylthiopropynyl,3-methylthiopropynyl, 2-ethylthioethynyl, 2-methyl-2-methylthioethynyl,1-methylthiobutynyl, 2-methylthiobutynyl, 3-methylthiobutynyl,2-ethylthiopropynyl, 3-methyl-3-methylthiopropynyl,4-methylthiopentynyl, 3-methylthiopentynyl, 2-methylthiopentynyl,1-methylthiopentynyl, 3,3-dimethylthiobutynyl, 2,2-dimethylthiobutynyl,1,1-dimethylthiobutynyl, 1-methyl-2-methylthiobutynyl,1,3-dimethylthiobutynyl, 2,3-dimethylthiobutynyl, 2-ethylthiobutynyl,1-methylthiohexynyl, 2-methylthiohexynyl, 3-methylthiohexynyl,4-methylthiohexynyl, 5-methylthiohexynyl, 1-propylthiobutynyl,4-methyl-4-methylthiopentynyl, 1-methylthioheptynyl,2-methylthioheptynyl, 3-methylthioheptynyl, 4-methylthioheptynyl,5-methylthioheptynyl, 6-methylthioheptynyl, 1-propylthiopentynyl,2-ethylthiohexynyl, 5-methyl-5-methylthiohexynyl, 3-methylthiooctynyl,4-methylthiooctynyl, 5-methylthiooctynyl, 6-methylthiooctynyl,1-propylthiohexynyl, 2-ethylthioheptynyl, 6-methyl-6-methylthioheptynyl,1-methylthiononynyl, 3-methylthiononynyl, 8-methylthiononynyl,3-ethylthiooctynyl, 3-methyl-7-methylthiooctynyl,7,7-dimethylthiooctynyl, 4-methyl-8-methythiononynyl,3,7-dimethyl-11-methylthiododecynyl,4,8-dimethyl-12-methylthiotridecynyl, 1-methylthiopentadecynyl,14-methylthiopentadecynyl, 13-methyl-13-methylthiotetradecynyl,15-methylthiohexadecynyl, 1-methylthioheptadecynyl, and3,7,11-trimethyl-15-methylthiohexadecynyl; an alkynyl group, which has 3to 20 carbons and is interrupted with one or two oxygen atoms, such as1-methyloxyethynyl, 2-methyloxyethynyl, 1l-methyloxypropynyl,2-methyloxypropynyl, 3-methyloxypropynyl, 2-ethyloxyethynyl,2-methyl-2-methyloxyethynyl, 1-methyloxybutynyl, 2-methyloxybutynyl,3-methyloxybutynyl, 2-ethyloxypropynyl, 3-methyl-3-methyloxypropynyl,4-methyloxypentynyl, 3-methyloxypentynyl, 2-methyloxypentynyl,1-methyloxypentynyl, 3,3-dimethyloxybutynyl, 2,2-dimethyloxybutynyl,1,1-dimethyloxybutynyl, 1-methyl-2-methyloxybutynyl,1,3-dimethyloxybutynyl, 2,3-dimethyloxybutynyl, 2-ethyloxybutynyl,1-methyloxyhexynyl, 2-methyloxyhexynyl, 3-methyloxyhexynyl,4-methyloxyhexynyl, 5-methyloxyhexynyl, 1-propyloxybutynyl,4-methyl-4-methyloxypentynyl, 1-methyloxyheptynyl, 2-methyloxyheptynyl,3-methyloxyheptynyl, 4-methyloxyheptynyl, 5-methyloxyheptynyl,6-methyloxyheptynyl, 1-propyloxypentynyl, 2-ethyloxyhexynyl,5-methyl-5-methyloxyhexynyl, 3-methyloxyoctynyl, 4-methyloxyoctynyl,5-methyloxyoctynyl, 6-methyloxyoctynyl, 1-propyloxyhexynyl,2-ethyloxyheptynyl, 6-methyl-6-methyloxyheptynyl, 1-methyloxynonynyl,3-methyloxynonynyl, 8-methyloxynonynyl, 3-ethyloxyoctynyl,3-methyl-7-methyloxyoctynyl, 7,7-dimethyloxyoctynyl,4-methyl-8-methyoxynonynyl, 3,7-dimethyl-11-methyloxydodecynyl,4,8-dimethyl-12-methyloxytridecynyl, 1-methyloxypentadecynyl,14-methyloxypentadecynyl, 13-methyl-13-methyloxytetradecynyl,15-methyloxyhexadecynyl, 1-methyloxyheptadecynyl, and3,7,11-trimethyl-15-methyloxyhexadecynyl; an alkynyl group, which has 3to 20 carbons and is interrupted with one or two nitrogen atoms, such as1-(N-methylamino)ethynyl, 2-(N-methylamio)ethynyl,1-(N-methylamino)propynyl, 2-(N-methylamino)propynyl,3-(N-methylamino)propynyl, 2-(N-ethylamino)ethynyl,2-(N,N-dimethylamino)ethynyl, 1-(N-methylamino)butynyl,2-(N-methylamino)butynyl, 3-(N-methylamino)butynyl,2-(N-ethylamino)propynyl, 3-(N,N-dimethylamino)propynyl,4-(N-methylamino)pentynyl, 3-(N-methylamino)pentynyl,2-(N-methylamino)pentynyl, 1-(N-methylamino)pentynyl,3-(N,N-dimethylamino)butynyl, 2-(N,N-dimethylamino)butynyl,1-(N,N-dimethylamino)butynyl, 1-methyl-2-(N-methylamino)butynyl,1,3-di(N-methylamino)butynyl, 2,3-di(N-methylamino)butynyl,2-(N-ethylamino)butynyl, 1-(N-methylamino)hexynyl,2-(N-methylamino)hexynyl, 3-(N-methylamino)hexynyl,4-(N-methylamino)hexynyl, 5-(N-methylamino)hexynyl,1-(N-propylamino)butynyl, 4-methyl-4-(N-methylamino)pentynyl,1-(N-methylamino)heptynyl, 2-(N-methylamino)heptynyl,3-(N-methylamino)heptynyl, 4-(N-methylamino)heptynyl,5-(N-methylamino)heptynyl, 6-(N-methylamino)heptynyl,1-(N-propylamino)pentynyl, 2-(N-ethylamino)hexynyl,5-methyl-5-(N-methylamino)hexynyl, 3-(N-methylamino)octynyl,4-(N-methylamino)octynyl, 5-(N-methylamino)octynyl,6-(N-methylamino)octynyl, 1-(N-propylamino)hexynyl,2-(N-ethylamino)heptynyl, 6-methyl-6-(N-methylamino)heptynyl,1-(N-methylamino)nonynyl, 3-(N-methylamino)nonynyl,8-(N-methylamino)nonynyl, 3-(N-ethylamino)octynyl,3-methyl-7-(N-methylamino)octynyl, 7,7-di(N-methylamino)octynyl,4-methyl-8-(N-methylamino)nonynyl,3,7-dimethyl-11-(N-methylamino)dodecynyl,4,8-dimethyl-12-(N-methylamino)tridecynyl,1-(N-methylamino)pentadecynyl, 14-(N-methylamino)pentadecynyl,13-methyl-13-(N-methylamino)tetradecynyl, 15-(N-methylamino)hexadecynyl,1-(N-methylamino)heptadecynyl, and3,7,11-trimethyl-15-(N-methylamino)hexadecynyl; and preferably a C₃-C₁₀alkynyl group interrupted with a heteroatom(s).

[0248] In the above formulae the “C₂-C₂₀ alkynyl group substituted withan aryl group(s) or a heteroaryl group(s)” in the definition of R^(4a)and R¹¹ represents the C₂-C₂₀ alkynyl groups described hereinbeforesubstituted with the same or different 1 to 3 of the aryl groupsdescribed hereinbefore or the heteroaryl groups described hereinbefore.

[0249] In the above formulae the “C₂-C₂₀ alkenyl group” in thedefinition of R^(4a) and R¹¹ includes, for example, a straight orbranched chain alkenyl group having 2 to 20 carbons such as an ethenyl,2-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl,2-ethyl-2-propenyl, 2-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl,1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl,1-ethyl-3-butenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl,3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl,1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 2-hexenyl, 3-hexenyl,4-hexenyl, 5-hexenyl, heptenyl, 1-methylhexenyl, 2-methylhexenyl,3-methylhexenyl, 4-methylhexenyl, 5-methylhexenyl, 1-propylbutenyl,4,4-dimethylpentenyl, octenyl, 1-methylheptenyl, 2-methylheptenyl,3-methylheptenyl, 4-methylheptenyl, 5-methylheptenyl, 6-methylheptenyl,1-propylpentenyl, 2-ethylhexenyl, 5,5-dimethylhexenyl, nonenyl,3-methyloctenyl, 4-methyloctenyl, 5-methyloctenyl, 6-methyloctenyl,1-propylhexenyl, 2-ethylheptenyl, 6,6-dimethylheptenyl, decenyl,1-methylnonenyl, 3-methylnonenyl, 8-methylnonenyl, 3-ethyloctenyl,3,7-dimethyloctenyl, 7,7-dimethyloctenyl, undecenyl,4,8-dimethylnonenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl,3,7,11-trimethyldodecenyl, hexadecenyl, 4,8,12-trimethyltridecenyl,1-methylpentadecenyl, 14-methylpentadecenyl, 13,13-dimethyltetradecenyl,heptadecenyl, 15-methylhexadecenyl, octadecenyl, 1-methylheptadecenyl,nonadecenyl, icosenyl and 3,7,11,15-tetramethylhexadecenyl group;preferably a C₂-C₁₀ alkenyl group.

[0250] In the above formulae the “C₃-C₂₀ alkenyl group interrupted witha hetero atom(s)” in the definition of R^(4a) and R¹¹ represents theC₃-C₂₀ alkenyl groups which are described hereinbefore and interruptedwith the same or different 1 or 2 of heteroatoms such as a sulfur atom,an oxygen atom or a nitrogen atom. Examples of such a group include analkenyl group which has 3 to 20 carbons and is interrupted with one ortwo sulfur atoms, such as 1-methylthioethenyl, 2-methylthioethenyl,1-methylthiopropenyl, 2-methylthiopropenyl, 3-methylthiopropenyl,2-ethylthioethenyl, 2-methyl-2-methylthioethenyl, 1-methylthiobutenyl,2-methylthiobutenyl, 3-methylthiobutenyl, 2-ethylthiopropenyl,3-methyl-3-methylthiopropenyl, 4-methylthiopentenyl,3-methylthiopentenyl, 2-methylthiopentenyl, 1-methylthiopentenyl,3,3-dimethylthiobutenyl, 2,2-dimethylthiobutenyl,1,1-dimethylthiobutenyl, 1-methyl-2-methylthiobutenyl,1,3-dimethylthiobutenyl, 2,3-dimethylthiobutenyl, 2-ethylthiobutenyl,1-methylthiohexenyl, 2-methylthiohexenyl, 3-methylthiohexenyl,4-methylthiohexenyl, 5-methylthiohexenyl, 1-propylthiobutenyl,4-methyl-4-methylthiopentenyl, 1-methylthioheptenyl,2-methylthioheptenyl, 3-methylthioheptenyl, 4-methylthioheptenyl,5-methylthioheptenyl, 6-methylthioheptenyl, 1-propylthiopentenyl,2-ethylthiohexenyl, 5-methyl-5-methylthiohexenyl, 3-methylthiooctenyl,4-methylthiooctenyl, 5-methylthiooctenyl, 6-methylthiooctenyl,1-propylthiohexenyl, 2-ethylthioheptenyl, 6-methyl-6-methylthioheptenyl,1-methylthiononenyl, 3-methylthiononenyl, 8-methylthiononenyl,3-ethylthiooctenyl, 3-methyl-7-methylthiooctenyl,7,7-dimethylthiooctenyl, 4-methyl-8-methythiononenyl,3,7-dimethyl-11-methylthiododecenyl,4,8-dimethyl-12-methylthiotridecenyl, 1-methylthiopentadecenyl,14-methylthiopentadecenyl, 13-methyl-13-methylthiotetradecenyl,15-methylthiohexadecenyl, 1-methylthioheptadecenyl, and3,7,11-trimethyl-15-methylthiohexadecenyl; an alkenyl group, which has 3to 20 carbons and interrupted with one or two oxygen atoms, such as1-methyloxyethenyl, 2-methyloxyethenyl, 1-methyloxypropenyl,2-methyloxypropenyl, 3-methyloxypropenyl, 2-ethyloxyethenyl,2-methyl-2-methyloxyethenyl, 1-methyloxybutenyl, 2-methyloxybutenyl,3-methyloxybutenyl, 2-ethyloxypropenyl, 3-methyl-3-methyloxypropenyl,4-methyloxypentenyl, 3-methyloxypentenyl, 2-methyloxypentenyl,1-methyloxypentenyl, 3,3-dimethyloxybutenyl, 2,2-dimethyloxybutenyl,1,1-dimethyloxybutenyl, 1-methyl-2-methyloxybutenyl,1,3-dimethyloxybutenyl, 2,3-dimethyloxybutenyl, 2-ethyloxybutenyl,1-methyloxyhexenyl, 2-methyloxyhexenyl, 3-methyloxyhexenyl,4-methyloxyhexenyl, 5-methyloxyhexenyl, 1-propyloxybutenyl,4-methyl-4-methyloxypentenyl, 1-methyloxyheptenyl, 2-methyloxyheptenyl,3-methyloxyheptenyl, 4-methyloxyheptenyl, 5-methyloxyheptenyl,6-methyloxyheptenyl, 1-propyloxypentenyl, 2-ethyloxyhexenyl,5-methyl-5-methyloxyhexenyl, 3-methyloxyoctenyl, 4-methyloxyoctenyl,5-methyloxyoctenyl, 6-methyloxyoctenyl, 1-propyloxyhexenyl,2-ethyloxyheptenyl, 6-methyl-6-methyloxyheptenyl, 1-methyloxynonenyl,3-methyloxynonenyl, 8-methyloxynonenyl, 3-ethyloxyoctenyl,3-methyl-7-methyloxyoctenyl, 7,7-dimethyloxyoctenyl,4-methyl-8-methyloxynonenyl, 3,7-dimethyl-11-methyloxydodecenyl,4,8-dimethyl-12-methyloxytridecenyl, 1-methyloxypentadecenyl,14-methyloxypentadecenyl, 13-methyl-13-methyloxytetradecenyl,15-methyloxyhexadecenyl, 1-methyloxyheptadecenyl, and3,7,11-trimethyl-15-methyloxyhexadecenyl; an alkenyl group which has 3to 20 carbons and is interrupted with one or two nitrogen atoms, such as1-(N-methylamino)ethenyl, 2-(N-methylamio)ethenyl,1-(N-methylamino)propenyl, 2-(N-methylamino)propenyl,3-(N-methylamino)propenyl, 2-(N-ethylamino)ethenyl,2-(N,N-dimethylamino)ethenyl, 1-(N-methylamino)butenyl,2-(N-methylamino)butenyl, 3-(N-methylamino)butenyl,2-(N-ethylamino)propenyl, 3-(N,N-dimethylamino)propenyl,4-(N-methylamino)pentenyl, 3-(N-methylamino)pentenyl,2-(N-methylamino)pentenyl, l-(N-methylamino)pentenyl,3-(N,N-dimethylamino)butenyl, 2-(N,N-dimethylamino)butenyl,1-(N,N-dimethylamino)butenyl, 1-methyl-2-(N-methylamino)butenyl,1,3-di(N-methylamino)butenyl, 2,3-di(N-methylamino)butenyl,2-(N-ethylamino)butenyl, 1-(N-methylamino)hexenyl,2-(N-methylamino)hexenyl, 3-(N-methylamino)hexenyl,4-(N-methylamino)hexenyl, 5-(N-methylamino)hexenyl,1-(N-propylamino)butenyl, 4-methyl-4-(N-methylamino)pentenyl,1-(N-methylamino)heptenyl, 2-(N-methylamino)heptenyl,3-(N-methylamino)heptenyl, 4-(N-methylamino)heptenyl,5-(N-methylamino)heptenyl, 6-(N-methylamino)heptenyl,1-(N-propylamino)pentenyl, 2-(N-ethylamino)hexenyl,5-methyl-5-(N-methylamino)hexenyl, 3-(N-methylamino)octenyl,4-(N-methylamino)octenyl, 5-(N-methylamino)octenyl,6-(N-methylamino)octenyl, 1-(N-propylamino)hexenyl,2-(N-ethylamino)heptenyl, 6-methyl-6-(N-methylamino)heptenyl,1-(N-methylamino)nonenyl, 3-(N-methylamino)nonenyl,8-(N-methylamino)nonenyl, 3-(N-ethylamino)octenyl,3-methyl-7-(N-methylamino)octenyl, 7,7-di(N-methylamino)octenyl,4-methyl-8-(N-methylamino)nonenyl,3,7-dimethyl-11-(N-methylamino)dodecenyl,4,8-dimethyl-12-(N-methylamino)tridecenyl,1-(N-methylamino)pentadecenyl, 14-(N-methylamino)pentadecenyl,13-methyl-13-(N-methylamino)tetradecenyl, 15-(N-methylamino)hexadecenyl,1-(N-methylamino)heptadecenyl, and3,7,11-trimethyl-15-(N-methylamino)hexadecenyl; and preferably a C₃-C₁₀alkenyl group interrupted with a heteroatom(s).

[0251] In the above formulae the “C₂-C₂₀ alkenyl group substituted withan aryl group(s) or a heteroaryl group(s)” in the definition of R^(4a)and R¹¹ represents the C₂-C₂₀ alkenyl groups described hereinbeforesubstituted with the same or different 1 to 3 of the aryl groupsdescribed hereinbefore or the heteroaryl groups described hereinbefore.

[0252] In the above formulae the “C₂-C₂₀ alkyl group which issubstituted with an aryl group(s) or a heteroaryl group(s) andinterrupted with a heteroatom(s)” in the definition of R^(4a) and R¹¹represents the C₂-C₂₀ alkyl groups interrupted with a heteroatom(s),described hereinbefore and substituted with the same or different 1 to 3of the aryl groups described hereinbefore or the heteroaryl groupsdescribed hereinbefore.

[0253] The lipase employed in this invention is not particularly limitedand the preferred lipase is different depending on the startingmaterial, however, is typically obtained from Pseudomonas sp.,Pseudomonas fluorescens, Pseudomonas cepacia, Chromobacterium viscosum,Aspergillus niger, Aspergillus oryzae, Candida antarctica, Candidacylindracea, Candida lipolytica, Candida rugosa, Candida utilis,Penicillium roqueforti, Rhizopus arrhizus, Rhizopus delemar, Rhizopusjavanicus, Rhizomucor miehei, Rhizopus niveus, Humicola lanuginosa,Mucor Javanicus, Mucor miehei, Thermus aquaticus, Thermus flavus,Thermus thermophilus or the like; or human pancreas, hog pancreas,porcine pancreas or wheat germ. Partially or completely purified enzymemoiety and fixed enzyme can be employed and the most preferred lipase isfixed Pseudomonas sp. [for example, immobilized lipase from Pseudomonassp. (TOYOBO Kabusiki Kaisya)].

[0254] Preferred vinyl ester derivatives of the carboxylic acid offormula (XLIII, R¹¹COOCH═CH₂) employed in this invention are differentdepending on the starting material, however they are typically a vinylester of a straight chain aliphatic acid such as the vinyl ester ofn-hexanoic acid, vinyl ester of n-heptanoic acid, vinyl ester ofn-pentanoic acid, vinyl ester of acetic acid or the like; and the mostpreferred one is the vinyl ester of n-hexanoic acid.

[0255] When the compound of formula (I) has a basic group such as aminogroup, the pharmaceutically acceptable salt can be prepared by thereaction of compound (I) with an acid. When the compound of formula (I)has a carboxy group the pharmaceutically acceptable salt can be preparedby the reaction of compound (I) with a base.

[0256] The preferred salts based on a basic group include ahydrohalogenic acid salt such as a hydrofluoride, hydrochloride,hydrobromide or hydroiodide; an inorganic acid salt such as a nitrate,perchlorate, sulfate or phosphate; a lower alkanesulfonic acid salt suchas a methanesulfonate, trifluoromethanesulfonate or ethanesulfonate; anaryl sulfonic acid salt such as a benzenesulfonate orp-toluenesulfonate; an organic acid salt such as an acetate, maleate,fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate orthe like; an amino acid salt such as a glycine salt, lysine salt,arginine salt, ornithine salt, glutamic acid salt or aspartic acid saltand most preferably an organic acid salt.

[0257] On the other hand the preferred salts based on an acid groupincludes an alkali metal salt such as a sodium salt, potassium salt orlithium salt; an alkaline earth metal salt such as a calcium salt ormagnesium salt; a metal salt such as an aluminum salt or iron salt; aninorganic salt such as an ammonium salt; an amine salt such as at-octylamine salt, benzylamine salt, morpholine salt, glucosamine salt,phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucaminesalt, guanidine salt, diethylamine salt, triethylamine salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt,chloroprocaine salt, procaine salt, diethanolamine salt,N-benzylphenethylamine salt, piperazine salt, tetramethylammonium saltor tris(hydroxymethyl)aminomethane salt; and an amino acid salt such asa glycine salt, lysine salt, arginine salt, ornithine salt, glutamicacid salt or aspartic acid salt.

[0258] When the Compound (I), a pharmaceutically acceptable saltthereof, an ester thereof or other derivative thereof are allowed tostand so that they are opened to the atmosphere or are recrystallized,they may absorb water and water may be attached to them to form ahydrate.

[0259] The salts of the present invention encompass such hydrates.

[0260] The compounds of formula (I), pharmaceutically acceptable saltsthereof, esters thereof or other derivatives thereof have an asymmetriccarbon (s) and can exist as optical isomer(s). In this invention asingle optical isomer and a mixture of optical isomers are representedby the single chemical formula (I). The present invention encompassesthe optical isomers individually and mixtures thereof in optionalratios. For example, the compounds of formula (I), pharmaceuticallyacceptable salts thereof, esters thereof or other derivatives thereofhave the following partial chemical formula wherein the —NR¹R² group isattached to an asymmetric carbon and the preferred absoluteconfiguration at this asymmetric carbon is the R configuration.

[0261] In the above formulae the “ester” refers to an ester of acompound of formula (I) which has a group capable of being esterified.The ester includes the ester of a hydroxyl group and the ester of acarboxy group. Each ester residual group belongs to a general protectinggroup in chemical reactions or a protecting group capable of beingremoved by a biological process such as hydrolysis in vivo.

[0262] The “general protecting group in chemical reaction” can becleaved by a chemical process such as hydrogenolysis, hydrolysis,electrolysis or photolysis.

[0263] The “general protecting group in chemical reactions and the“protecting group capable of being removed by a biological process suchas hydrolysis in vivo” in the esters of a hydroxyl group have the samemeaning as that described above for a hydroxyl protecting group.

[0264] The “general protecting group in chemical reactions” in the esterof a carboxyl group preferably includes a lower alkyl group describedhereinbefore; a lower alkenyl group such as ethenyl, 1-propenyl,2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl,1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl,1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl,2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl,1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl,1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 4-hexenyl or 5-hexenyl; a lower alkynyl group such asethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl,1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl,1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 3-pentynyl,1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl,1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl,4-hexynyl or 5-hexynyl; a halogenated lower alkyl group describedhereinbefore; a hydroxy lower alkyl group such as 2-hydroxyethyl,2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl or4-hydroxybutyl; a lower aliphatic acyl-lower alkyl group such asacetylmethyl; an aralkyl group described hereinbefore; or a silyl groupdescribed hereinbefore.

[0265] The “protecting group capable of being removed by a biologicalprocess such as hydrolysis in vivo” can be cleaved by a biologicalprocess such as hydrolysis in the human body to afford a free acid or asalt thereof. Whether a derivative of formula (I) has such a protectinggroup can be easily determined. The derivative under investigation isadministered intravenously to a test animal such as a mouse or a rat andthe body fluids of the test animal are thereafter studied. If the parentcompound or a pharmacologically acceptable salt thereof is detected inthe body fluids of the test animal, the derivative under investigationis judged to have such a group. The “protecting group capable of beingremoved by a biological process such as hydrolysis in vivo” preferablyincludes a lower alkoxy lower alkyl group such as methoxyethyl,1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-(isopropoxy)ethyl,2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxyethyl,ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl ort-butoxymethyl; a lower alkoxy lower alkoxy lower alkyl group such as2-methoxyethoxymethyl; an aryloxy lower alkyl group such asphenoxymethyl; a halogenated lower alkoxy lower alkyl group such as2,2,2-trichloroethoxymethyl or bis(2-chloroethoxy)methyl; a loweralkoxycarbonyl lower alkyl group such as methoxycarbonylmethyl; a cyanolower alkyl group such as cyanomethyl or 2-cyanoethyl; a loweralkylthiomethyl group such as methylthiomethyl or ethylthiomethyl; anarylthiomethyl group such as phenylthiomethyl or naphthylthiomethyl; alower alkyl optionally substituted with a halogen atom(s) sulfonyl loweralkyl group such as 2-methanesulfonylethyl or2-trifluoromethanesulfonylethyl; an arylsulfonyl lower alkyl group suchas 2-benzenesulfonylethyl or 2-toluenesulfonylethyl; a 1-(acyloxy) loweralkyl group described hereinbefore; a phthalidyl group describedhereinbefore; an aryl group described hereinbefore; a lower alkyl groupdescribed hereinbefore; a carboxyalkyl group such as carboxymethyl; andan amide-formation residual group of an amino acid such asphenylalanine.

[0266] When the compound of formula (I) in this invention has an aminogroup and/or a carboxyl group, such a compound can be converted to aderivative other than a pharmacologically acceptable salt or an esterdescribed hereinbefore. The “other derivative” refers to such aderivative, for example, an amide derivative such as an acyl group.

[0267] Typical examples of compounds of formula (I) in this inventionare listed in the following Table 1 and 2. Typical examples of compoundof formula (La) and (La-1) in this invention are listed in Table 3 and4. The present invention is not limited to these examples.

[0268] The following abbreviation are used in these lists: Ac: acetylgroup; Boc: t-butoxycarbonyl group; Bpyrr: benzopyrrolyl group; Bu:butyl group; iBu: isobutyl group; Bz: benzyl group; Bzt: benzothienylgroup; Et: ethyl group; Fur: furyl group; cHx: cyclohexyl group; Me:methyl group; Np(1): naphthalen-1-yl group; Np(2): naphthalen-²-ylgroup; Ph: phenyl group; cPn: cyclopentyl group; Pr: propyl group; iPr:isopropyl group; Pyr: pyridyl group; TBDMS: t-butyldimethylsilyl group;and The: thienyl group. TABLE 1 (Ia)

Exemp. Compd. No. R¹ R² R³ R⁴ n —X—Y—R⁵ R⁶ R⁷ 1-1 H H H Me 1 —(CH₂)₅-cHxH H 1-2 H H H Me 1 —(CH₂)₆-cHx H H 1-3 H H H Me 1 —CH═CH—(CH₂)₃-cHx H H1-4 H H H Me 1 —CH═CH—(CH₂)₄-cHx H H 1-5 H H H Me 1 —C≡C—(CH₂)₃-cHx H H1-6 H H H Me 1 —C≡C—(CH₂)₄-cHx H H 1-7 H H H Me 1 —CO—(CH₂)₄-cHx H H 1-8H H H Me 1 —CO—(CH₂)₅-cHx H H 1-9 H H H Me 1 —CH(OH)—(CH₂)₄-cHx H H 1-10H H H Me 1 —CH(OH)—(CH₂)₅-cHx H H 1-11 H H H Me 1 -4-(cHx-CH₂O)Ph H H1-12 H H H Me 1 -(4-BzO-Ph) H H 1-13 H H H Me 1 —C≡C—CH₂O-cPn H H 1-14 HH H Me 1 —C≡C—(CH₂)₂O-cPn H H 1-15 H H H Me 1 —C≡C—CH₂O-cHx H H 1-16 H HH Me 1 —C≡C—(CH₂)₂O-cHx H H 1-17 H H H Me 1 —C≡C—CH₂O-Ph H H 1-18 H H HMe 1 —C≡C—(CH₂)₂O-Ph H H 1-19 H H H Me 2 —(CH₂)₂-cHx H H 1-20 H H Me Me2 —(CH₂)₂-cHx H H 1-21 Me H H Me 2 —(CH₂)₂-cHx H H 1-22 CO₂Me H H Me 2—(CH₂)₂-cHx H H 1-23 H H H Me 2 —(CH₂)₂-(4-F-cHx) H H 1-24 H H H Me 2—(CH₂)₂-(4-Me-cHx) H H 1-25 H H H Me 2 —(CH₂)₂-(4-Et-cHx) H H 1-26 H H HMe 2 —(CH₂)₂-(4-CF₃-cHx) H H 1-27 H H H Me 2 —(CH₂)₂-(4-MeO-cHx) H H1-28 H H H Me 2 —(CH₂)₂-(4-EtO-cHx) H H 1-29 H H H Me 2—(CH₂)₂-(4-MeS-cHx) H H 1-30 H H H Me 2 —(CH₂)₂-(4-cHx-cHx) H H 1-31 H HH Me 2 —(CH₂)₂-(4-Ph-cHx) H H 1-32 H H H Me 2 —(CH₂)₂-Ph H H 1-33 H H MeMe 2 —(CH₂)₂-Ph H H 1-34 Me H H Me 2 —(CH₂)₂-Ph H H 1-35 CO₂Me H H Me 2—(CH₂)₂-Ph H H 1-36 H H H Me 2 —(CH₂)₂-(4-F-Ph) H H 1-37 H H H Me 2—(CH₂)₂-(4-Me-Ph) H H 1-38 H H H Me 2 —(CH₂)₂-(4-Et-Ph) H H 1-39 H H HMe 2 —(CH₂)₂-(4-CF₃-Ph) H H 1-40 H H H Me 2 —(CH₂)₂-(4-MeO-Ph) H H 1-41H H H Me 2 —(CH₂)₂-(4-EtO-Ph) H H 1-42 H H H Me 2 —(CH₂)₂-(4-MeS-Ph) H H1-43 H H H Me 2 —(CH₂)₂-(4-cHx-Ph) H H 1-44 H H H Me 2 —(CH₂)₂-(4-Ph-Ph)H H 1-45 H H H Me 2 —(CH₂)₃-cHx H H 1-46 H H Me Me 2 —(CH₂)₃-cHx H H1-47 Me H H Me 2 —(CH₂)₃-cHx H H 1-48 CO₂Me H H Me 2 —(CH₂)₃-cHx H H1-49 H H H Me 2 —(CH₂)₃-(4-F-cHx) H H 1-50 H H H Me 2 —(CH₂)₃-(4-Me-cHx)H H 1-51 H H H Me 2 —(CH₂)₃-(4-Et-cHx) H H 1-52 H H H Me 2—(CH₂)₃-(4-CF₃-cHx) H H 1-53 H H H Me 2 —(CH₂)₃-(4-MeO-cHx) H H 1-54 H HH Me 2 —(CH₂)₃-(4-EtO-cHx) H H 1-55 H H H Me 2 —(CH₂)₃-(4-MeS-cHx) H H1-56 H H H Me 2 —(CH₂)₃-(4-cHx-cHx) H H 1-57 H H H Me 2—(CH₂)₃-(4-Ph-cHx) H H 1-58 H H H Me 2 —(CH₂)₃-Ph H H 1-59 H H Me Me 2—(CH₂)₃-Ph H H 1-60 Me H H Me 2 —(CH₂)₃-Ph H H 1-61 CO₂Me H H Me 2—(CH₂)₃-Ph H H 1-62 H H H Me 2 —(CH₂)₃-(4-F-Ph) H H 1-63 H H H Me 2—(CH₂)₃-(4-Me-Ph) H H 1-64 H H H Me 2 —(CH₂)₃-(4-Et-Ph) H H 1-65 H H HMe 2 —(CH₂)₃-(4-CF₃-Ph) H H 1-66 H H H Me 2 —(CH₂)₃-(4-MeO-Ph) H H 1-67H H H Me 2 —(CH₂)₃-(4-EtO-Ph) H H 1-68 H H H Me 2 —(CH₂)₃-(4-MeS-Ph) H H1-69 H H H Me 2 —(CH₂)₃-(4-cHx-Ph) H H 1-70 H H H Me 2 —(CH₂)₃-(4-Ph-Ph)H H 1-71 H H H Me 2 —(CH₂)₄-cHx H H 1-72 H H Me Me 2 —(CH₂)₄-cHx H H1-73 Me H H Me 2 —(CH₂)₄-cHx H H 1-74 CO₂Me H H Me 2 —(CH₂)₄-cHx H H1-75 H H H Me 2 —(CH₂)₄-(4-F-cHx) H H 1-76 H H H Me 2 —(CH₂)₄-(4-Me-cHx)H H 1-77 H H H Me 2 —(CH₂)₄-(4-Et-cHx) H H 1-78 H H H Me 2—(CH₂)₄-(4-CF₃-cHx) H H 1-79 H H H Me 2 —(CH₂)₄-(4-MeO-cHx) H H 1-80 H HH Me 2 —(CH₂)₄-(4-EtO-cHx) H H 1-81 H H H Me 2 —(CH₂)₄-(4-MeS-cHx) H H1-82 H H H Me 2 —(CH₂)₄-(4-cHx-cHx) H H 1-83 H H H Me 2—(CH₂)₄-(4-Ph-cHx) H H 1-84 H H H Me 2 —(CH₂)₄-Ph H H 1-85 H H Me Me 2—(CH₂)₄-Ph H H 1-86 Me H H Me 2 —(CH₂)₄-Ph H H 1-87 CO₂Me H H Me 2—(CH₂)₄-Ph H H 1-88 H H H Me 2 —(CH₂)₄-(4-F-Ph) H H 1-89 H H H Me 2—(CH₂)₄-(4-Me-Ph) H H 1-90 H H H Me 2 —(CH₂)₄-(4-Et-Ph) H H 1-91 H H HMe 2 —(CH₂)₄-(4-CF₃-Ph) H H 1-92 H H H Me 2 —(CH₂)₄-(4-MeO-Ph) H H 1-93H H H Me 2 —(CH₂)₄-(4-EtO-Ph) H H 1-94 H H H Me 2 —(CH₂)₄-(4-MeS-Ph) H H1-95 H H H Me 2 —(CH₂)₄-(4-cHx-Ph) H H 1-96 H H H Me 2 —(CH₂)₄-(4-Ph-Ph)H H 1-97 H H H Me 2 —(CH₂)₅-cPn H H 1-98 H H H Me 2 —(CH₂)₅-cHx H H 1-99H H H Me 2 —(CH₂)₅-cHx Me H 1-100 H H H Me 2 —(CH₂)₅-cHx H Me 1-101 H HH Me 2 —(CH₂)₅-cHx F H 1-102 H H H Me 2 —(CH₂)₅-cHx H F 1-103 H H Me Me2 —(CH₂)₅-cHx H H 1-104 Me H H Me 2 —(CH₂)₅-cHx H H 1-105 CO₂Me H H Me 2—(CH₂)₅-cHx H H 1-106 H H H Me 2 —(CH₂)₅-(3-F-cHx) H H 1-107 H H H Me 2—(CH₂)₅-(4-F-cHx) H H 1-108 H H H Me 2 —(CH₂)₅-(4-Cl-cHx) H H 1-109 H HH Me 2 —(CH₂)₅-(4-Br-cHx) H H 1-110 H H H Me 2 —(CH₂)₅-(3-Me-cHx) H H1-111 H H H Me 2 —(CH₂)₅-(4-Me-cHx) H H 1-112 H H H Me 2—(CH₂)₅-(3-Et-cHx) H H 1-113 H H H Me 2 —(CH₂)₅-(4-Et-cHx) H H 1-114 H HH Me 2 —(CH₂)₅-(3-Pr-cHx) H H 1-115 H H H Me 2 —(CH₂)₅-(4-Pr-cHx) H H1-116 H H H Me 2 —(CH₂)₅-(4-iPr-cHx) H H 1-117 H H H Me 2—(CH₂)₅-(3-Bu-cHx) H H 1-118 H H H Me 2 —(CH₂)₅-(4-Bu-cHx) H H 1-119 H HH Me 2 —(CH₂)₅-(3-CF₃-cHx) H H 1-120 H H H Me 2 —(CH₂)₅-(4-CF₃-cHx) H H1-121 H H H Me 2 —(CH₂)₅-(3-MeO-cHx) H H 1-122 H H H Me 2—(CH₂)₅-(4-MeO-cHx) H H 1-123 H H H Me 2 —(CH₂)₅-(3-EtO-cHx) H H 1-124 HH H Me 2 —(CH₂)₅-(4-EtO-cHx) H H 1-125 H H H Me 2 —(CH₂)₅-(3-PrO-cHx) HH 1-126 H H H Me 2 —(CH₂)₅-(4-PrO-cHx) H H 1-127 H H H Me 2—(CH₂)₅-(3-iPrO-cHx) H H 1-128 H H H Me 2 —(CH₂)₅-(4-iPrO-cHx) H H 1-129H H H Me 2 —(CH₂)₅-[3-(2-Et-PrO)-cHx] H H 1-130 H H H Me 2—(CH₂)₅-[4-(2-Et-PrO)-cHx] H H 1-131 H H H Me 2 —(CH₂)₅-(3-iBuO-cHx) H H1-132 H H H Me 2 —(CH₂)₅-(4-iBuO-cHx) H H 1-133 H H H Me 2—(CH₂)₅-(3-MeS-cHx) H H 1-134 H H H Me 2 —(CH₂)₅-(4-MeS-cHx) H H 1-135 HH H Me 2 —(CH₂)₅-(3-EtS-cHx) H H 1-136 H H H Me 2 —(CH₂)₅-(4-EtS-cHx) HH 1-137 H H H Me 2 —(CH₂)₅-(3-PrS-cHx) H H 1-138 H H H Me 2—(CH₂)₅-(4-PrS-cHx) H H 1-139 H H H Me 2 —(CH₂)₅-(3-iPrS-cHx) H H 1-140H H H Me 2 —(CH₂)₅-(4-iPrS-cHx) H H 1-141 H H H Me 2—(CH₂)₅-[3-(2-Et-PrS)-cHx] H H 1-142 H H H Me 2—(CH₂)₅-[4-(2-Et-PrS)-cHx] H H 1-143 H H H Me 2 —(CH₂)₅-(3-iBuS-cHx) H H1-144 H H H Me 2 —(CH₂)₅-(4-iBuS-cHx) H H 1-145 H H H Me 2—(CH₂)₅-(3-cHx-cHx) H H 1-146 H H H Me 2 —(CH₂)₅-(4-cHx-cHx) H H 1-147 HH H Me 2 —(CH₂)₅-(3-Ph-cHx) H H 1-148 H H H Me 2 —(CH₂)₅-(4-Ph-cHx) H H1-149 H H H Me 2 —(CH₂)₅-(2,4-diMe-cHx) H H 1-150 H H H Me 2—(CH₂)₅-(3,4-diMe-cHx) H H 1-151 H H H Me 2 —(CH₂)₅-(3,5-diMe-cHx) H H1-152 H H H Me 2 —(CH₂)₅-Ph H H 1-153 H H H Me 2 —(CH₂)₅-Ph Me H 1-154 HH H Me 2 —(CH₂)₅-Ph H Me 1-155 H H H Me 2 —(CH₂)₅-Ph F H 1-156 H H H Me2 —(CH₂)₅-Ph H F 1-157 H H Me Me 2 —(CH₂)₅-Ph H H 1-158 Me H H Me 2—(CH₂)₅-Ph H H 1-159 CO₂Me H H Me 2 —(CH₂)₅-Ph H H 1-160 H H H Me 2—(CH₂)₅-(3-F-Ph) H H 1-161 H H H Me 2 —(CH₂)₅-(4-F-Ph) H H 1-162 H H HMe 2 —(CH₂)₅-(4-Cl-Ph) H H 1-163 H H H Me 2 —(CH₂)₅-(4-Br-Ph) H H 1-164H H H Me 2 —(CH₂)₅-(3-Me-Ph) H H 1-165 H H H Me 2 —(CH₂)₅-(4-Me-Ph) H H1-166 H H H Me 2 —(CH₂)₅-(3-Et-Ph) H H 1-167 H H H Me 2—(CH₂)₅-(4-Et-Ph) H H 1-168 H H H Me 2 —(CH₂)₅-(3-Pr-Ph) H H 1-169 H H HMe 2 —(CH₂)₅-(4-Pr-Ph) H H 1-170 H H H Me 2 —(CH₂)₅-(3-iPr-Ph) H H 1-171H H H Me 2 —(CH₂)₅-(4-iPr-Ph) H H 1-172 H H H Me 2 —(CH₂)₅-(3-Bu-Ph) H H1-173 H H H Me 2 —(CH₂)₅-(4-Bu-Ph) H H 1-174 H H H Me 2—(CH₂)₅-(3-CF₃-Ph) H H 1-175 H H H Me 2 —(CH₂)₅-(4-CF₃-Ph) H H 1-176 H HH Me 2 —(CH₂)₅-(3-MeO-Ph) H H 1-177 H H H Me 2 —(CH₂)₅-(4-MeO-Ph) H H1-178 H H H Me 2 —(CH₂)₅-(3-EtO-Ph) H H 1-179 H H H Me 2—(CH₂)₅-(4-EtO-Ph) H H 1-180 H H H Me 2 —(CH₂)₅-(3-PrO-Ph) H H 1-181 H HH Me 2 —(CH₂)₅-(4-PrO-Ph) H H 1-182 H H H Me 2 —(CH₂)₅-(3-iPrO-Ph) H H1-183 H H H Me 2 —(CH₂)₅-(4-iPrO-Ph) H H 1-184 H H H Me 2—(CH₂)₅-[3-(2-Et-PrO)-Ph] H H 1-185 H H H Me 2 —(CH₂)₅-[4-(2-Et-PrO)-Ph]H H 1-186 H H H Me 2 —(CH₂)₅-(3-iBuO-Ph) H H 1-187 H H H Me 2—(CH₂)₅-(4-iBuO-Ph) H H 1-188 H H H Me 2 —(CH₂)₅-(3-MeS-Ph) H H 1-189 HH H Me 2 —(CH₂)₅-(4-MeS-Ph) H H 1-190 H H H Me 2 —(CH₂)₅-(3-EtS-Ph) H H1-191 H H H Me 2 —(CH₂)₅-(4-EtS-Ph) H H 1-192 H H H Me 2—(CH₂)₅-(3-PrS-Ph) H H 1-193 H H H Me 2 —(CH₂)₅-(4-PrS-Ph) H H 1-194 H HH Me 2 —(CH₂)₅-(3-iPrS-Ph) H H 1-195 H H H Me 2 —(CH₂)₅-(4-iPrS-Ph) H H1-196 H H H Me 2 —(CH₂)₅-[3-(2-Et-PrS)-Ph] H H 1-197 H H H Me 2—(CH₂)₅-[4-(2-Et-PrS)-Ph] H H 1-198 H H H Me 2 —(CH₂)₅-(3-iBuS-Ph) H H1-199 H H H Me 2 —(CH₂)₅-(4-iBuS-Ph) H H 1-200 H H H Me 2—(CH₂)₅-(3-cHx-Ph) H H 1-201 H H H Me 2 —(CH₂)₅-(4-cHx-Ph) H H 1-202 H HH Me 2 —(CH₂)₅-(3-Ph-Ph) H H 1-203 H H H Me 2 —(CH₂)₅-(4-Ph-Ph) H H1-204 H H H Me 2 —(CH₂)₅-(2,4-diMe-Ph) H H 1-205 H H H Me 2—(CH₂)₅-(3,4-diMe-Ph) H H 1-206 H H H Me 2 —(CH₂)₅-(3,5-diMe-Ph) H H1-207 H H H Me 2 —(CH₂)₅-Np(1) H H 1-208 H H H Me 2 —(CH₂)₅-Np(2) H H1-209 H H H Me 2 —(CH₂)₆-cPn H H 1-210 H H H Me 2 —(CH₂)₆-cHx H H 1-211H H H Me 2 —(CH₂)₆-cHx Me H 1-212 H H H Me 2 —(CH₂)₆-cHx H Me 1-213 H HH Me 2 —(CH₂)₆-cHx F H 1-214 H H H Me 2 —(CH₂)₆-cHx H F 1-215 H H Me Me2 —(CH₂)₆-cHx H H 1-216 Me H H Me 2 —(CH₂)₆-cHx H H 1-217 CO₂Me H H Me 2—(CH₂)₆-cHx H H 1-218 H H H Me 2 —(CH₂)₆-(3-F-cHx) H H 1-219 H H H Me 2—(CH₂)₆-(4-F-cHx) H H 1-220 H H H Me 2 —(CH₂)₆-(4-Cl-cHx) H H 1-221 H HH Me 2 —(CH₂)₆-(4-Br-cHx) H H 1-222 H H H Me 2 —(CH₂)₆-(3-Me-cHx) H H1-223 H H H Me 2 —(CH₂)₆-(4-Me-cHx) H H 1-224 H H H Me 2—(CH₂)₆-(3-Et-cHx) H H 1-225 H H H Me 2 —(CH₂)₆-(4-Et-cHx) H H 1-226 H HH Me 2 —(CH₂)₆-(3-Pr-cHx) H H 1-227 H H H Me 2 —(CH₂)₆-(4-Pr-cHx) H H1-228 H H H Me 2 —(CH₂)₆-(4-iPr-cHx) H H 1-229 H H H Me 2—(CH₂)₆-(3-Bu-cHx) H H 1-230 H H H Me 2 —(CH₂)₆-(4-Bu-cHx) H H 1-231 H HH Me 2 —(CH₂)₆-(3-CF₃-cHx) H H 1-232 H H H Me 2 —(CH₂)₆-(4-CF₃-cHx) H H1-233 H H H Me 2 —(CH₂)₆-(3-MeO-cHx) H H 1-234 H H H Me 2—(CH₂)₆-(4-MeO-cHx) H H 1-235 H H H Me 2 —(CH₂)₆-(3-EtO-cHx) H H 1-236 HH H Me 2 —(CH₂)₆-(4-EtO-cHx) H H 1-237 H H H Me 2 —(CH₂)₆-(3-PrO-cHx) HH 1-238 H H H Me 2 —(CH₂)₆-(4-PrO-cHx) H H 1-239 H H H Me 2—(CH₂)₆-(3-iPrO-cHx) H H 1-240 H H H Me 2 —(CH₂)₆-(4-iPrO-cHx) H H 1-241H H H Me 2 —(CH₂)₆-[3-(2-Et-PrO)-cHx] H H 1-242 H H H Me 2—(CH₂)₆-[4-(2-Et-PrO)-cHx] H H 1-243 H H H Me 2 —(CH₂)₆-(3-iBuO-cHx) H H1-244 H H H Me 2 —(CH₂)₆-(4-iBuO-cHx) H H 1-245 H H H Me 2—(CH₂)₆-(3-MeS-cHx) H H 1-246 H H H Me 2 —(CH₂)₆-(4-MeS-cHx) H H 1-247 HH H Me 2 —(CH₂)₆-(3-EtS-cHx) H H 1-248 H H H Me 2 —(CH₂)₆-(4-EtS-cHx) HH 1-249 H H H Me 2 —(CH₂)₆-(3-PrS-cHx) H H 1-250 H H H Me 2—(CH₂)₆-(4-PrS-cHx) H H 1-251 H H H Me 2 —(CH₂)₆-(3-iPrS-cHx) H H 1-252H H H Me 2 —(CH₂)₆-(4-iPrS-cHx) H H 1-253 H H H Me 2—(CH₂)₆-[3-(2-Et-PrS)-cHx] H H 1-254 H H H Me 2—(CH₂)₆-[4-(2-Et-PrS)-cHx] H H 1-255 H H H Me 2 —(CH₂)₆-(3-iBuS-cHx) H H1-256 H H H Me 2 —(CH₂)₆-(4-iBuS-cHx) H H 1-257 H H H Me 2—(CH₂)₆-(3-cHx-cHx) H H 1-258 H H H Me 2 —(CH₂)₆-(4-cHx-cHx) H H 1-259 HH H Me 2 —(CH₂)₆-(3-Ph-cHx) H H 1-260 H H H Me 2 —(CH₂)₆-(4-Ph-cHx) H H1-261 H H H Me 2 —(CH₂)₆-(2,4-diMe-cHx) H H 1-262 H H H Me 2—(CH₂)₆-(3,4-diMe-cHx) H H 1-263 H H H Me 2 —(CH₂)₆-(3,5-diMe-cHx) H H1-264 H H H Me 2 —(CH₂)₆-Ph H H 1-265 H H H Me 2 —(CH₂)₆-Ph Me H 1-266 HH H Me 2 —(CH₂)₆-Ph H Me 1-267 H H H Me 2 —(CH₂)₆-Ph F H 1-268 H H H Me2 —(CH₂)₆-Ph H F 1-269 H H Me Me 2 —(CH₂)₆-Ph H H 1-270 Me H H Me 2—(CH₂)₆-Ph H H 1-271 CO₂Me H H Me 2 —(CH₂)₆-Ph H H 1-272 H H H Me 2—(CH₂)₆-(3-F-Ph) H H 1-273 H H H Me 2 —(CH₂)₆-(4-F-Ph) H H 1-274 H H HMe 2 —(CH₂)₆-(4-Cl-Ph) H H 1-275 H H H Me 2 —(CH₂)₆-(4-Br-Ph) H H 1-276H H H Me 2 —(CH₂)₆-(3-Me-Ph) H H 1-277 H H H Me 2 —(CH₂)₆-(4-Me-Ph) H H1-278 H H H Me 2 —(CH₂)₆-(3-Et-Ph) H H 1-279 H H H Me 2—(CH₂)₆-(4-Et-Ph) H H 1-280 H H H Me 2 —(CH₂)₆-(3-Pr-Ph) H H 1-281 H H HMe 2 —(CH₂)₆-(4-Pr-Ph) H H 1-282 H H H Me 2 —(CH₂)₆-(3-iPr-Ph) H H 1-283H H H Me 2 —(CH₂)₆-(4-iPr-Ph) H H 1-284 H H H Me 2 —(CH₂)₆-(3-Bu-Ph) H H1-285 H H H Me 2 —(CH₂)₆-(4-Bu-Ph) H H 1-286 H H H Me 2—(CH₂)₆-(3-CF₃-Ph) H H 1-287 H H H Me 2 —(CH₂)₆-(4-CF₃-Ph) H H 1-288 H HH Me 2 —(CH₂)₆-(3-MeO-Ph) H H 1-289 H H H Me 2 —(CH₂)₆-(4-MeO-Ph) H H1-290 H H H Me 2 —(CH₂)₆-(3-EtO-Ph) H H 1-291 H H H Me 2—(CH₂)₆-(4-EtO-Ph) H H 1-292 H H H Me 2 —(CH₂)₆-(3-PrO-Ph) H H 1-293 H HH Me 2 —(CH₂)₆-(4-PrO-Ph) H H 1-294 H H H Me 2 —(CH₂)₆-(3-iPrO-Ph) H H1-295 H H H Me 2 —(CH₂)₆-(4-iPrO-Ph) H H 1-296 H H H Me 2—(CH₂)₆-[3-(2-Et-PrO)-Ph] H H 1-297 H H H Me 2 —(CH₂)₆-[4-(2-Et-PrO)-Ph]H H 1-298 H H H Me 2 —(CH₂)₆-(3-iBuO-Ph) H H 1-299 H H H Me 2—(CH₂)₆-(4-iBuO-Ph) H H 1-300 H H H Me 2 —(CH₂)₆-(3-MeS-Ph) H H 1-301 HH H Me 2 —(CH₂)₆-(4-MeS-Ph) H H 1-302 H H H Me 2 —(CH₂)₆-(3-EtS-Ph) H H1-303 H H H Me 2 —(CH₂)₆-(4-EtS-Ph) H H 1-304 H H H Me 2—(CH₂)₆-(3-PrS-Ph) H H 1-305 H H H Me 2 —(CH₂)₆-(4-PrS-Ph) H H 1-306 H HH Me 2 —(CH₂)₆-(3-iPrS-Ph) H H 1-307 H H H Me 2 —(CH₂)₆-(4-iPrS-Ph) H H1-308 H H H Me 2 —(CH₂)₆-[3-(2-Et-PrS)-Ph] H H 1-309 H H H Me 2—(CH₂)₆-[4-(2-Et-PrS)-Ph] H H 1-310 H H H Me 2 —(CH₂)₆-(3-iBuS-Ph) H H1-311 H H H Me 2 —(CH₂)₆-(4-iBuS-Ph) H H 1-312 H H H Me 2—(CH₂)₆-(3-cHx-Ph) H H 1-313 H H H Me 2 —(CH₂)₆-(4-cHx-Ph) H H 1-314 H HH Me 2 —(CH₂)₆-(3-Ph-Ph) H H 1-315 H H H Me 2 —(CH₂)₆-(4-Ph-Ph) H H1-316 H H H Me 2 —(CH₂)₆-(2,4-diMe-Ph) H H 1-317 H H H Me 2—(CH₂)₆-(3,4-diMe-Ph) H H 1-318 H H H Me 2 —(CH₂)₆-(3,5-diMe-Ph) H H1-319 H H H Me 2 —(CH₂)₆-Np(1) H H 1-320 H H H Me 2 —(CH₂)₆-Np(2) H H1-321 H H H Me 2 —(CH₂)₇-cHx H H 1-322 H H Me Me 2 —(CH₂)₇-cHx H H 1-323Me H H Me 2 —(CH₂)₇-cHx H H 1-324 CO₂Me H H Me 2 —(CH₂)₇-cHx H H 1-325 HH H Me 2 —(CH₂)₇-(4-F-cHx) H H 1-326 H H H Me 2 —(CH₂)₇-(4-Me-cHx) H H1-327 H H H Me 2 —(CH₂)₇-(4-Et-cHx) H H 1-328 H H H Me 2—(CH₂)₇-(4-CF₃-cHx) H H 1-329 H H H Me 2 —(CH₂)₇-(4-MeO-cHx) H H 1-330 HH H Me 2 —(CH₂)₇-(4-EtO-cHx) H H 1-331 H H H Me 2 —(CH₂)₇-(4-MeS-cHx) HH 1-332 H H H Me 2 —(CH₂)₇-(4-cHx-cHx) H H 1-333 H H H Me 2—(CH₂)₇-(4-Ph-cHx) H H 1-334 H H H Me 2 —(CH₂)₇-Ph H H 1-335 H H Me Me 2—(CH₂)₇-Ph H H 1-336 Me H H Me 2 —(CH₂)₇-Ph H H 1-337 CO₂Me H H Me 2—(CH₂)₇-Ph H H 1-338 H H H Me 2 —(CH₂)₇-(4-F-Ph) H H 1-339 H H H Me 2—(CH₂)₇-(4-Me-Ph) H H 1-340 H H H Me 2 —(CH₂)₇-(4-Et-Ph) H H 1-341 H H HMe 2 —(CH₂)₇-(4-CF₃-Ph) H H 1-342 H H H Me 2 —(CH₂)₇-(4-MeO-Ph) H H1-343 H H H Me 2 —(CH₂)₇-(4-EtO-Ph) H H 1-344 H H H Me 2—(CH₂)₇-(4-MeS-Ph) H H 1-345 H H H Me 2 —(CH₂)₇-(4-cHx-Ph) H H 1-346 H HH Me 2 —(CH₂)₇-(4-Ph-Ph) H H 1-347 H H H Me 2 —(CH₂)₅-cHx H H 1-348 H HMe Me 2 —(CH₂)₈-cHx H H 1-349 Me H H Me 2 —(CH₂)₈-cHx H H 1-350 CO₂Me HH Me 2 —(CH₂)₅-cHx H H 1-351 H H H Me 2 —(CH₂)₈-(4-F-cHx) H H 1-352 H HH Me 2 —(CH₂)₈-(4-Me-cHx) H H 1-353 H H H Me 2 —(CH₂)₈-(4-Et-cHx) H H1-354 H H H Me 2 —(CH₂)₈-(4-CF₃-cHx) H H 1-355 H H H Me 2—(CH₂)₈-(4-MeO-cHx) H H 1-356 H H H Me 2 —(CH₂)₈-(4-EtO-cHx) H H 1-357 HH H Me 2 —(CH₂)₈-(4-MeS-cHx) H H 1-358 H H H Me 2 —(CH₂)₈-(4-cHx-cHx) HH 1-359 H H H Me 2 —(CH₂)₈-(4-Ph-cHx) H H 1-360 H H H Me 2 —(CH₂)₈-Ph HH 1-361 H H Me Me 2 —(CH₂)₈-Ph H H 1-362 Me H H Me 2 —(CH₂)₈-Ph H H1-363 CO₂Me H H Me 2 —(CH₂)₈-Ph H H 1-364 H H H Me 2 —(CH₂)₈-(4-F-Ph) HH 1-365 H H H Me 2 —(CH₂)₈-(4-Me-Ph) H H 1-366 H H H Me 2—(CH₂)₈-(4-Et-Ph) H H 1-367 H H H Me 2 —(CH₂)₈-(4-CF₃-Ph) H H 1-368 H HH Me 2 —(CH₂)₈-(4-MeO-Ph) H H 1-369 H H H Me 2 —(CH₂)₈-(4-EtO-Ph) H H1-370 H H H Me 2 —(CH₂)₈-(4-MeS-Ph) H H 1-371 H H H Me 2—(CH₂)₈-(4-cHx-Ph) H H 1-372 H H H Me 2 —(CH₂)₈-(4-Ph-Ph) H H 1-373 H HH Me 2 —(CH₂)₃—O-cHx H H 1-374 H H Me Me 2 —(CH₂)₃—O-cHx H H 1-375 Me HH Me 2 —(CH₂)₃—O-cHx H H 1-376 CO₂Me H H Me 2 —(CH₂)₃—O-cHx H H 1-377 HH H Me 2 —(CH₂)₃—O-(4-F-cHx) H H 1-378 H H H Me 2 —(CH₂)₃—O-(4-Me-cHx) HH 1-379 H H H Me 2 —(CH₂)₃—O-(4-Et-cHx) H H 1-380 H H H Me 2—(CH₂)₃—O-(4-CF₃-cHx) H H 1-381 H H H Me 2 —(CH₂)₃—O-(4-MeO-cHx) H H1-382 H H H Me 2 —(CH₂)₃—O-(4-EtO-cHx) H H 1-383 H H H Me 2—(CH₂)₃—O-(4-MeS-cHx) H H 1-384 H H H Me 2 —(CH₂)₃—O-(4-cHx-cHx) H H1-385 H H H Me 2 —(CH₂)₃—O-(4-Ph-cHx) H H 1-386 H H H Me 2 —(CH₂)₃—O-PhH H 1-387 H H Me Me 2 —(CH₂)₃—O-Ph H H 1-388 Me H H Me 2 —(CH₂)₃—O-Ph HH 1-389 CO₂Me H H Me 2 —(CH₂)₃—O-Ph H H 1-390 H H H Me 2—(CH₂)₃—O-(4-F-Ph) H H 1-391 H H H Me 2 —(CH₂)₃—O-(4-Me-Ph) H H 1-392 HH H Me 2 —(CH₂)₃—O-(4-Et-Ph) H H 1-393 H H H Me 2 —(CH₂)₃—O-(4-CF₃-Ph) HH 1-394 H H H Me 2 —(CH₂)₃—O-(4-MeO-Ph) H H 1-395 H H H Me 2—(CH₂)₃—O-(4-EtO-Ph) H H 1-396 H H H Me 2 —(CH₂)₃—O-(4-MeS-Ph) H H 1-397H H H Me 2 —(CH₂)₃—O-(4-cHx-Ph) H H 1-398 H H H Me 2 —(CH₂)₃—O-(4-Ph-Ph)H H 1-399 H H H Me 2 —(CH₂)₄—O-cPn H H 1-400 H H H Me 2 —(CH₂)₄—O-cHx HH 1-401 H H H Me 2 —(CH₂)₄—O-cHx Me H 1-402 H H H Me 2 —(CH₂)₄—O-cHx HMe 1-403 H H H Me 2 —(CH₂)₄—O-cHx F H 1-404 H H H Me 2 —(CH₂)₄—O-cHx H F1-405 H H Me Me 2 —(CH₂)₄—O-cHx H H 1-406 Me H H Me 2 —(CH₂)₄—O-cHx H H1-407 CO₂Me H H Me 2 —(CH₂)₄—O-cHx H H 1-408 H H H Me 2—(CH₂)₄—O-(3-F-cHx) H H 1-409 H H H Me 2 —(CH₂)₄—O-(4-F-cHx) H H 1-410 HH H Me 2 —(CH₂)₄—O-(4-Cl-cHx) H H 1-411 H H H Me 2 —(CH₂)₄—O-(4-Br-cHx)H H 1-412 H H H Me 2 —(CH₂)₄—O-(3-Me-cHx) H H 1-413 H H H Me 2—(CH₂)₄—O-(4-Me-cHx) H H 1-414 H H H Me 2 —(CH₂)₄—O-(3-Et-cHx) H H 1-415H H H Me 2 —(CH₂)₄—O-(4-Et-cHx) H H 1-416 H H H Me 2—(CH₂)₄—O-(3-Pr-cHx) H H 1-417 H H H Me 2 —(CH₂)₄—O-(4-Pr-cHx) H H 1-418H H H Me 2 —(CH₂)₄—O-(4-iPr-cHx) H H 1-419 H H H Me 2—(CH₂)₄—O-(3-Bu-cHx) H H 1-420 H H H Me 2 —(CH₂)₄—O-(4-Bu-cHx) H H 1-421H H H Me 2 —(CH₂)₄—O-(3-CF₃-cHx) H H 1-422 H H H Me 2—(CH₂)₄—O-(4-CF₃-cHx) H H 1-423 H H H Me 2 —(CH₂)₄—O-(3-MeO-cHx) H H1-424 H H H Me 2 —(CH₂)₄—O-(4-MeO-cHx) H H 1-425 H H H Me 2—(CH₂)₄—O-(3-EtO-cHx) H H 1-426 H H H Me 2 —(CH₂)₄—O-(4-EtO-cHx) H H1-427 H H H Me 2 —(CH₂)₄—O-(3-PrO-cHx) H H 1-428 H H H Me 2—(CH₂)₄—O-(4-PrO-cHx) H H 1-429 H H H Me 2 —(CH₂)₄—O-(3-iPrO-cHx) H H1-430 H H H Me 2 —(CH₂)₄—O-(4-iPr-cHx) H H 1-431 H H H Me 2—(CH₂)₄—O-[3-(2-Et-PrO)-cHx] H H 1-432 H H H Me 2—(CH₂)₄—O-[4-(2-Et-PrO)-cHx] H H 1-433 H H H Me 2 —(CH₂)₄—O-(3-iBuO-cHx)H H 1-434 H H H Me 2 —(CH₂)₄—O-(4-iBuO-cHx) H H 1-435 H H H Me 2—(CH₂)₄—O-(3-MeS-cHx) H H 1-436 H H H Me 2 —(CH₂)₄—O-(4-MeS-cHx) H H1-437 H H H Me 2 —(CH₂)₄—O-(3-EtS-cHx) H H 1-438 H H H Me 2—(CH₂)₄—O-(4-EtS-cHx) H H 1-439 H H H Me 2 —(CH₂)₄—O-(3-PrS-cHx) H H1-440 H H H Me 2 —(CH₂)₄—O-(4-PrS-cHx) H H 1-441 H H H Me 2—(CH₂)₄—O-(3-iPrS-cHx) H H 1-442 H H H Me 2 —(CH₂)₄—O-(4-iPrS-cHx) H H1-443 H H H Me 2 —(CH₂)₄—O-[3-(2-Et-PrS)-cHx] H H 1-444 H H H Me 2—(CH₂)₄—O-[4-(2-Et-PrS)-cHx] H H 1-445 H H H Me 2 —(CH₂)₄—O-(3-iBuS-cHx)H H 1-446 H H H Me 2 —(CH₂)₄—O-(4-iBuS-cHx) H H 1-447 H H H Me 2—(CH₂)₄—O-(3-cHx-cHx) H H 1-448 H H H Me 2 —(CH₂)₄—O-(4-cHx-cHx) H H1-449 H H H Me 2 —(CH₂)₄—O-(3-Ph-cHx) H H 1-450 H H H Me 2—(CH₂)₄—O-(4-Ph-cHx) H H 1-451 H H H Me 2 —(CH₂)₄—O-(2,4-diMe-cHx) H H1-452 H H H Me 2 —(CH₂)₄—O-(3,4-diMe-cHx) H H 1-453 H H H Me 2—(CH₂)₄—O-(3,5-diMe-cHx) H H 1-454 H H H Me 2 —(CH₂)₄—O-Ph H H 1-455 H HH Me 2 —(CH₂)₄—O-Ph Me H 1-456 H H H Me 2 —(CH₂)₄—O-Ph H Me 1-457 H H HMe 2 —(CH₂)₄—O-Ph F H 1-458 H H H Me 2 —(CH₂)₄—O-Ph H F 1-459 H H Me Me2 —(CH₂)₄—O-Ph H H 1-460 Me H H Me 2 —(CH₂)₄—O-Ph H H 1-461 CO₂Me H H Me2 —(CH₂)₄—O-Ph H H 1-462 H H H Me 2 —(CH₂)₄—O-(3-F-Ph) H H 1-463 H H HMe 2 —(CH₂)₄—O-(4-F-Ph) H H 1-464 H H H Me 2 —(CH₂)₄—O-(4-Cl-Ph) H H1-465 H H H Me 2 —(CH₂)₄—O-(4-Br-Ph) H H 1-466 H H H Me 2—(CH₂)₄—O-(3-Me-Ph) H H 1-467 H H H Me 2 —(CH₂)₄—O-(4-Me-Ph) H H 1-468 HH H Me 2 —(CH₂)₄—O-(3-Et-Ph) H H 1-469 H H H Me 2 —(CH₂)₄—O-(4-Et-Ph) HH 1-470 H H H Me 2 —(CH₂)₄—O-(3-Pr-Ph) R H 1-471 H H H Me 2—(CH₂)₄—O-(4-Pr-Ph) H H 1-472 H H H Me 2 —(CH₂)₄—O-(3-iPr-Ph) H H 1-473H H H Me 2 —(CH₂)₄—O-(4-iPr-Ph) H H 1-474 H H H Me 2 —(CH₂)₄—O-(3-Bu-Ph)H H 1-475 H H H Me 2 —(CH₂)₄—O-(4-Bu-Ph) H H 1-476 H H H Me 2—(CH₂)₄—O-(3-CF₃-Ph) H H 1-477 H H H Me 2 —(CH₂)₄—O-(4-CF₃-Ph) H H 1-478H H H Me 2 —(CH₂)₄—O-(3-MeO-Ph) H H 1-479 H H H Me 2—(CH₂)₄—O-(4-MeO-Ph) H H 1-480 H H H Me 2 —(CH₂)₄—O-(3-EtO-Ph) H H 1-481H H H Me 2 —(CH₂)₄—O-(4-EtO-Ph) H H 1-482 H H H Me 2—(CH₂)₄—O-(3-PrO-Ph) H H 1-483 H H H Me 2 —(CH₂)₄—O-(4-PrO-Ph) H H 1-484H H H Me 2 —(CH₂)₄—O-(3-iPrO-Ph) H H 1-485 H H H Me 2—(CH₂)₄—O-(4-iPrO-Ph) H H 1-486 H H H Me 2 —(CH₂)₄—O-[3-(2-Et-PrO)-Ph] HH 1-487 H H H Me 2 —(CH₂)₄—O-[4-(2-Et-PrO)-Ph] H H 1-488 H H H Me 2—(CH₂)₄—O-(3-iBuO-Ph) H H 1-489 H H H Me 2 —(CH₂)₄—O-(4-iBuO-Ph) H H1-490 H H H Me 2 —(CH₂)₄—O-(3-MeS-Ph) H H 1-491 H H H Me 2—(CH₂)₄—O-(4-MeS-Ph) H H 1-492 H H H Me 2 —(CH₂)₄—O-(3-EtS-Ph) H H 1-493H H H Me 2 —(CH₂)₄—O-(4-EtS-Ph) H H 1-494 H H H Me 2—(CH₂)₄—O-(3-PrS-Ph) H H 1-495 H H H Me 2 —(CH₂)₄—O-(4-PrS-Ph) H H 1-496H H H Me 2 —(CH₂)₄—O-(3-iPrS-Ph) H H 1-497 H H H Me 2—(CH₂)₄—O-(4-iPrS-Ph) H H 1-498 H H H Me 2 —(CH₂)₄—O-[3-(2-Et-PrS)-Ph] HH 1-499 H H H Me 2 —(CH₂)₄—O-[4-(2-Et-PrS)-Ph] H H 1-500 H H H Me 2—(CH₂)₄—O-(3-iBuS-Ph) H H 1-501 H H H Me 2 —(CH₂)₄—O-(4-iBuS-Ph) H H1-502 H H H Me 2 —(CH₂)₄—O-(3-cHx-Ph) H H 1-503 H H H Me 2—(CH₂)₄—O-(4-cHx-Ph) H H 1-504 H H H Me 2 —(CH₂)₄—O-(3-Ph-Ph) H H 1-505H H H Me 2 —(CH₂)₄—O-(4-Ph-Ph) H H 1-506 H H H Me 2—(CH₂)₄—O-(2,4-diMe-Ph) H H 1-507 H H H Me 2 —(CH₂)₄—O-(3,4-diMe-Ph) H H1-508 H H H Me 2 —(CH₂)₄—O-(3,5-diMe-Ph) H H 1-509 H H H Me 2—(CH₂)₅—O-cHx H H 1-510 H H H Me 2 —(CH₂)₅—O-Ph H H 1-511 H H H Me 2—(CH₂)₆—O-cHx H H 1-512 H H H Me 2 —(CH₂)₆—O-Ph H H 1-513 H H H Me 2—(CH₂)₃—OCH₂-cHx H H 1-514 H H Me Me 2 —(CH₂)₃—OCH₂-cHx H H 1-515 Me H HMe 2 —(CH₂)₃—OCH₂-cHx H H 1-516 CO₂Me H H Me 2 —(CH₂)₃—OCH₂-cHx H H1-517 H H H Me 2 —(CH₂)₃—OCH₂-(4-F-cHx) H H 1-518 H H H Me 2—(CH₂)₃—OCH₂-(4-Me-cHx) H H 1-519 H H H Me 2 —(CH₂)₃—OCH₂-(4-Et-cHx) H H1-520 H H H Me 2 —(CH₂)₃—OCH₂-(4-CF₃-cHx) H H 1-521 H H H Me 2—(CH₂)₃—OCH₂-(4-MeO-cHx) H H 1-522 H H H Me 2 —(CH₂)₃—OCH₂-(4-EtO-cHx) HH 1-523 H H H Me 2 —(CH₂)₃—OCH₂-(4-MeS-cHx) H H 1-524 H H H Me 2—(CH₂)₃—OCH₂-(4-cHx-cHx) H H 1-525 H H H Me 2 —(CH₂)₃—OCH₂-(4-Ph-cHx) HH 1-526 H H H Me 2 —(CH₂)₃—OCH₂-Ph H H 1-527 H H Me Me 2 —(CH₂)₃—OCH₂-PhH H 1-528 Me H H Me 2 —(CH₂)₃—OCH₂-Ph H H 1-529 CO₂Me H H Me 2—(CH₂)₃—OCH₂-Ph H H 1-530 H H H Me 2 —(CH₂)₃—OCH₂-(4-F-Ph) H H 1-531 H HH Me 2 —(CH₂)₃—OCH₂-(4-Me-Ph) H H 1-532 H H H Me 2—(CH₂)₃—OCH₂-(4-Et-Ph) H H 1-533 H H H Me 2 —(CH₂)₃—OCH₂-(4-CF₃-Ph) H H1-534 H H H Me 2 —(CH₂)₃—OCH₂-(4-MeO-Ph) H H 1-535 H H H Me 2—(CH₂)₃—OCH₂-(4-EtO-Ph) H H 1-536 H H H Me 2 —(CH₂)₃—OCH₂-(4-MeS-Ph) H H1-537 H H H Me 2 —(CH₂)₃—OCH₂-(4-cHx-Ph) H H 1-538 H H H Me 2—(CH₂)₃—OCH₂-(4-Ph-Ph) H H 1-539 H H H Me 2 —(CH₂)₄—OCH₂-cPn H H 1-540 HH H Me 2 —(CH₂)₄—OCH₂-cHx H H 1-541 H H H Me 2 —(CH₂)₄—OCH₂-cHx Me H1-542 H H H Me 2 —(CH₂)₄—OCH₂-cHx H Me 1-543 H H H Me 2 —(CH₂)₄—OCH₂-cHxF H 1-544 H H H Me 2 —(CH₂)₄—OCH₂-cHx H F 1-545 H H Me Me 2—(CH₂)₄—OCH₂-cHx H H 1-546 Me H H Me 2 —(CH₂)₄—OCH₂-cHx H H 1-547 CO₂MeH H Me 2 —(CH₂)₄—OCH₂-cHx H H 1-548 H H H Me 2 —(CH₂)₄—OCH₂-(3-F-cHx) HH 1-549 H H H Me 2 —(CH₂)₄—OCH₂-(4-F-cHx) H H 1-550 H H H Me 2—(CH₂)₄—OCH₂-(4-Cl-cHx) H H 1-551 H H H Me 2 —(CH₂)₄—OCH₂-(4-Br-cHx) H H1-552 H H H Me 2 —(CH₂)₄—OCH₂-(3-Me-cHx) H H 1-553 H H H Me 2—(CH₂)₄—OCH₂-(4-Me-cHx) H H 1-554 H H H Me 2 —(CH₂)₄—OCH₂-(3-Et-cHx) H H1-555 H H H Me 2 —(CH₂)₄—OCH₂-(4-Et-cHx) H H 1-556 H H H Me 2—(CH₂)₄—OCH₂-(3-Pr-cHx) H H 1-557 H H H Me 2 —(CH₂)₄—OCH₂-(4-Pr-cHx) H H1-558 H H H Me 2 —(CH₂)₄—OCH₂-(4-iPr-cHx) H H 1-559 H H H Me 2—(CH₂)₄—OCH₂-(3-Bu-cHx) H H 1-560 H H H Me 2 —(CH₂)₄—OCH₂-(4-Bu-cHx) H H1-561 H H H Me 2 —(CH₂)₄—OCH₂-(3-CF₃-cHx) H H 1-562 H H H Me 2—(CH₂)₄—OCH₂-(4-CF₃-cHx) H H 1-563 H H H Me 2 —(CH₂)₄—OCH₂-(3-MeO-cHx) HH 1-564 H H H Me 2 —(CH₂)₄—OCH₂-(4-MeO-cHx) H H 1-565 H H H Me 2—(CH₂)₄—OCH₂-(3-EtO-cHx) H H 1-566 H H H Me 2 —(CH₂)₄—OCH₂-(4-EtO-cHx) HH 1-567 H H H Me 2 —(CH₂)₄—OCH₂-(3-PrO-cHx) H H 1-568 H H H Me 2—(CH₂)₄—OCH₂-(4-PrO-cHx) H H 1-569 H H H Me 2 —(CH₂)₄—OCH₂-(3-iPrO-cHx)H H 1-570 H H H Me 2 —(CH₂)₄—OCH₂-(4-iPrO-cHx) H H 1-571 H H H Me 2—(CH₂)₄—OCH₂-[3-(2-Et-PrO)-cHx] H H 1-572 H H H Me 2—(CH₂)₄—OCH₂-[4-(2-Et-PrO)-cHx] H H 1-573 H H H Me 2—(CH₂)₄—OCH₂-(3-iBuO-cHx) H H 1-574 H H H Me 2 —(CH₂)₄—OCH₂-(4-iBuO-cHx)H H 1-575 H H H Me 2 —(CH₂)₄—OCH₂-(3-MeS-cHx) H H 1-576 H H H Me 2—(CH₂)₄—OCH₂-(4-MeS-cHx) H H 1-577 H H H Me 2 —(CH₂)₄—OCH₂-(3-EtS-cHx) HH 1-578 H H H Me 2 —(CH₂)₄—OCH₂-(4-EtS-cHx) H H 1-579 H H H Me 2—(CH₂)₄—OCH₂-(3-PrS-cHx) H H 1-580 H H H Me 2 —(CH₂)₄—OCH₂-(4-PrS-cHx) HH 1-581 H H H Me 2 —(CH₂)₄—OCH₂-(3-iPrS-cHx) H H 1-582 H H H Me 2—(CH₂)₄—OCH₂-(4-iPrS-cHx) H H 1-583 H H H Me 2—(CH₂)₄—OCH₂-[3-(2-Et-PrS)-cHx] H H 1-584 H H H Me 2—(CH₂)₄—OCH₂-[4-(2-Et-PrS)-cHx] H H 1-585 H H H Me 2—(CH₂)₄—OCH₂-(3-iBuS-cHx) H H 1-586 H H H Me 2 —(CH₂)₄—OCH₂-(4-iBuS-cHx)H H 1-587 H H H Me 2 —(CH₂)₄—OCH₂-(3-cHx-cHx) H H 1-588 H H H Me 2—(CH₂)₄—OCH₂-(4-cHx-cHx) H H 1-589 H H H Me 2 —(CH₂)₄—OCH₂-(3-Ph-cHx) HH 1-590 H H H Me 2 —(CH₂)₄—OCH₂-(4-Ph-cHx) H H 1-591 H H H Me 2—(CH₂)₄—OCH₂-(2,4-diMe-cHx) H H 1-592 H H H Me 2—(CH₂)₄—OCH₂-(3,4-diMe-cHx) H H 1-593 H H H Me 2—(CH₂)₄—OCH₂-(3,5-diMe-cHx) H H 1-594 H H H Me 2 —(CH₂)₄—OCH₂-Ph H H1-595 H H H Me 2 —(CH₂)₄—OCH₂-Ph Me H 1-596 H H H Me 2 —(CH₂)₄—OCH₂-Ph HMe 1-597 H H H Me 2 —(CH₂)₄—OCH₂-Ph F H 1-598 H H H Me 2 —(CH₂)₄—OCH₂-PhH F 1-599 H H Me Me 2 —(CH₂)₄—OCH₂-Ph H H 1-600 Me H H Me 2—(CH₂)₄—OCH₂-Ph H H 1-601 CO₂Me H H Me 2 —(CH₂)₄—OCH₂-Ph H H 1-602 H H HMe 2 —(CH₂)₄—OCH₂-(3-F-Ph) H H 1-603 H H H Me 2 —(CH₂)₄—OCH₂-(4-F-Ph) HH 1-604 H H H Me 2 —(CH₂)₄—OCH₂-(4-Cl-Ph) H H 1-605 H H H Me 2—(CH₂)₄—OCH₂-(4-Br-Ph) H H 1-606 H H H Me 2 —(CH₂)₄—OCH₂-(3-Me-Ph) H H1-607 H H H Me 2 —(CH₂)₄—OCH₂-(4-Me-Ph) H H 1-608 H H H Me 2—(CH₂)₄—OCH₂-(3-Et-Ph) H H 1-609 H H H Me 2 —(CH₂)₄—OCH₂-(4-Et-Ph) H H1-610 H H H Me 2 —(CH₂)₄—OCH₂-(3-Pr-Ph) H H 1-611 H H H Me 2—(CH₂)₄—OCH₂-(4-Pr-Ph) H H 1-612 H H H Me 2 —(CH₂)₄—OCH₂-(3-iPr-Ph) H H1-613 H H H Me 2 —(CH₂)₄—OCH₂-(4-iPr-Ph) H H 1-614 H H H Me 2—(CH₂)₄—OCH₂-(3-Bu-Ph) H H 1-615 H H H Me 2 —(CH₂)₄—OCH₂-(4-Bu-Ph) H H1-616 H H H Me 2 —(CH₂)₄—OCH₂-(3-CF₃-Ph) H H 1-617 H H H Me 2—(CH₂)₄—OCH₂-(4-CF₃-Ph) H H 1-618 H H H Me 2 —(CH₂)₄—OCH₂-(3-MeO-Ph) H H1-619 H H H Me 2 —(CH₂)₄—OCH₂-(4-MeO-Ph) H H 1-620 H H H Me 2—(CH₂)₄—OCH₂-(3-EtO-Ph) H H 1-62 1 H H H Me 2 —(CH₂)₄—OCH₂-(4-EtO-Ph) HH 1-622 H H H Me 2 —(CH₂)₄—OCH₂-(3-PrO-Ph) H H 1-623 H H H Me 2—(CH₂)₄—OCH₂-(4-PrO-Ph) H H 1-624 H H H Me 2 —(CH₂)₄—OCH₂-(3-iPrO-Ph) HH 1-625 H H H Me 2 —(CH₂)₄—OCH₂-(4-iPrO-Ph) H H 1-626 H H H Me 2—(CH₂)₄—OCH₂-[3-(2-Et-PrO)-Ph] H H 1-627 H H H Me 2—(CH₂)₄—OCH₂-[4-(2-Et-PrO)-Ph] H H 1-628 H H H Me 2—(CH₂)₄—OCH₂-(3-iBuO-Ph) H H 1-629 H H H Me 2 —(CH₂)₄—OCH₂-(4-iBuO-Ph) HH 1-630 H H H Me 2 —(CH₂)₄—OCH₂-(3-MeS-Ph) H H 1-631 H H H Me 2—(CH₂)₄—OCH₂-(4-MeS-Ph) H H 1-632 H H H Me 2 —(CH₂)₄—OCH₂-(3-EtS-Ph) H H1-633 H H H Me 2 —(CH₂)₄—OCH₂-(4-EtS-Ph) H H 1-634 H H H Me 2—(CH₂)₄—OCH₂-(3-PrS-Ph) H H 1-635 H H H Me 2 —(CH₂)₄—OCH₂-(4-PrS-Ph) H H1-636 H H H Me 2 —(CH₂)₄—OCH₂-(3-iPrS-Ph) H H 1-637 H H H Me 2—(CH₂)₄—OCH₂-(4-iPrS-Ph) H H 1-638 H H H Me 2—(CH₂)₄—OCH₂-[3-(2-Et-PrS)-Ph] H H 1-639 H H H Me 2—(CH₂)₄—OCH₂-[4-(2-Et-PrS)-Ph] H H 1-640 H H H Me 2—(CH₂)₄—OCH₂-(3-iBuS-Ph) H H 1-641 H H H Me 2 —(CH₂)₄—OCH₂-(4-iBuS-Ph) HH 1-642 H H H Me 2 —(CH₂)₄—OCH₂-(3-cHx-Ph) H H 1-643 H H H Me 2—(CH₂)₄—OCH₂-(4-cHx-Ph) H H 1-644 H H H Me 2 —(CH₂)₄—OCH₂-(3-Ph-Ph) H H1-645 H H H Me 2 —(CH₂)₄—OCH₂-(4-Ph-Ph) H H 1-646 H H H Me 2—(CH₂)₄—OCH₂-(2,4-diMe-Ph) H H 1-647 H H H Me 2—(CH₂)₄—OCH₂-(3,4-diMe-Ph) H H 1-648 H H H Me 2—(CH₂)₄—OCH₂-(3,5-diMe-Ph) H H 1-649 H H H Me 2 —(CH₂)₅—OCH₂-cHx H H1-650 H H H Me 2 —(CH₂)₅—OCH₂-Ph H H 1-65 1 H H H Me 2 —(CH₂)₆—OCH₂-cHxH H 1-652 H H H Me 2 —(CH₂)₆—OCH₂-Ph H H 1-653 H H H Me 2 —CH═CH-cHx H H1-654 H H H Me 2 —CH═CH-Ph H H 1-655 H H H Me 2 —CH═CH—(CH₂)₂-cHx H H1-656 H H H Me 2 —CH═CH—(CH₂)₂-Ph H H 1-657 H H H Me 2 —CH═CH—(CH₂)₃-cHxH H 1-658 H H Me Me 2 —CH═CH—(CH₂)₃-cHx H H 1-659 Me H H Me 2—CH═CH—(CH₂)₃-cHx H H 1-660 CO₂Me H H Me 2 —CH═CH—(CH₂)₃-cHx H H 1-661 HH H Me 2 —CH═CH—(CH₂)₃-(4-F-cHx) H H 1-662 H H H Me 2—CH═CH—(CH₂)₃-(4-Me-cHx) H H 1-663 H H H Me 2 —CH═CH—(CH₂)₃-(4-Et-cHx) HH 1-664 H H H Me 2 —CH═CH—(CH₂)₃-(4-CF₃-cHx) H H 1-665 H H H Me 2—CH═CH—(CH₂)₃-(4-MeO-cHx) H H 1-666 H H H Me 2 —CH═CH—(CH₂)₃-(4-EtO-cHx)H H 1-667 H H H Me 2 —CH═CH—(CH₂)₃-(4-MeS-cHx) H H 1-668 H H H Me 2—CH═CH—(CH₂)₃-(4-cHx-cHx) H H 1-669 H H H Me 2 —CH═CH—(CH₂)₃-(4-Ph-cHx)H H 1-670 H H H Me 2 —CH═CH—(CH₂)₃-Ph H H 1-671 H H Me Me 2—CH═CH—(CH₂)₃-Ph H H 1-672 Me H H Me 2 —CH═CH—(CH₂)₃-Ph H H 1-673 CO₂MeH H Me 2 —CH═CH—(CH₂)₃-Ph H H 1-674 H H H Me 2 —CH═CH—(CH₂)₃-(4-F-Ph) HH 1-675 H H H Me 2 —CH═CH—(CH₂)₃-(4-Me-Ph) H H 1-676 H H H Me 2—CH═CH—(CH₂)₃-(4-Et-Ph) H H 1-677 H H H Me 2 —CH═CH—(CH₂)₃-(4-CF₃-Ph) HH 1-678 H H H Me 2 —CH═CH—(CH₂)₃-(4-MeO-Ph) H H 1-679 H H H Me 2—CH═CH—(CH₂)₃-(4-EtO-Ph) H H 1-680 H H H Me 2 —CH═CH—(CH₂)₃-(4-MeS-Ph) HH 1-681 H H H Me 2 —CH═CH—(CH₂)₃-(4-cHx-Ph) H H 1-682 H H H Me 2—CH═CH—(CH₂)₃-(4-Ph-Ph) H H 1-683 H H H Me 2 —CH═CH—(CH₂)₄-cHx H H 1-684H H Me Me 2 —CH═CH—(CH₂)₄-cHx H H 1-685 Me H H Me 2 —CH═CH—(CH₂)₄-cHx HH 1-686 CO₂Me H H Me 2 —CH═CH—(CH₂)₄-cHx H H 1-687 H H H Me 2—CH═CH—(CH₂)₄-(4-F-cHx) H H 1-688 H H H Me 2 —CH═CH—(CH₂)₄-(4-Me-cHx) HH 1-689 H H H Me 2 —CH═CH—(CH₂)₄-(4-Et-cHx) H H 1-690 H H H Me 2—CH═CH—(CH₂)₄-(4-CF₃-cHx) H H 1-691 H H H Me 2 —CH═CH—(CH₂)₄-(4-MeO-cHx)H H 1-692 H H H Me 2 —CH═CH—(CH₂)₄-(4-EtO-cHx) H H 1-693 H H H Me 2—CH═CH—(CH₂)₄-(4-MeS-cHx) H H 1-694 H H H Me 2 —CH═CH—(CH₂)₄-(4-cHx-cHx)H H 1-695 H H H Me 2 —CH═CH—(CH₂)₄-(4-Ph-cHx) H H 1-696 H H H Me 2—CH═CH—(CH₂)₄-Ph H H 1-697 H H Me Me 2 —CH═CH—(CH₂)₄-Ph H H 1-698 Me H HMe 2 —CH═CH—(CH₂)₄-Ph H H 1-699 CO₂Me H H Me 2 —CH═CH—(CH₂)₄-Ph H H1-700 H H H Me 2 —CH═CH—(CH₂)₄-(4-F-Ph) H H 1-701 H H H Me 2—CH═CH—(CH₂)₄-(4-Me-Ph) H H 1-702 H H H Me 2 —CH═CH—(CH₂)₄-(4-Et-Ph) H H1-703 H H H Me 2 —CH═CH—(CH₂)₄-(4-CF₃-Ph) H H 1-704 H H H Me 2—CH═CH—(CH₂)₄-(4-MeO-Ph) H H 1-705 H H H Me 2 —CH═CH—(CH₂)₄-(4-EtO-Ph) HH 1-706 H H H Me 2 —CH═CH—(CH₂)₄-(4-MeS-Ph) H H 1-707 H H H Me 2—CH═CH—(CH₂)₄-(4-cHx-Ph) H H 1-708 H H H Me 2 —CH═CH—(CH₂)₄-(4-Ph-Ph) HH 1-709 H H H Me 2 —CH═CH—(CH₂)₅-cHx H H 1-710 H H H Me 2—CH═CH—(CH₂)₅-Ph H H 1-711 H H H Me 2 —CH═CH—(CH₂)₆-cHx H H 1-712 H H HMe 2 —CH═CH—(CH₂)₆-Ph H H 1-713 H H H Me 2 —C═C—CH₂O-cHx H H 1-714 H H HMe 2 —C═C—CH₂O-Ph H H 1-715 H H H Me 2 —C≡C-(GH2)₂O-cHx H H 1-716 H H HMe 2 —C≡C—(CH₂)₂O-Ph H H 1-717 H H H Me 2 —C≡C—CHX H H 1-718 H H Me Me 2—C≡C-cHx H H 1-719 Me H H Me 2 —C≡C-cHx H H 1-720 CO₂Me H H Me 2—C≡C-cHx H H 1-721 H H H Me 2 —C≡C-(4-F-cHx) H H 1-722 H H H Me 2—C≡C-(4-Me-cHx) H H 1-723 H H H Me 2 —C≡C-(4-Et-cHx) H H 1-724 H H H Me2 —C≡C-(4-CF₃-cHx) H H 1-725 H H H Me 2 —C≡C-(4-MeO-cHx) H H 1-726 H H HMe 2 —C≡C-(4-EtO-cHx) H H 1-727 H H H Me 2 —C≡C-(4-MeS-cHx) H H 1-728 HH H Me 2 —C≡C-(4-cHx-cHx) H H 1-729 H H H Me 2 —C≡C-(4-Ph-cHx) H H 1-730H H H Me 2 —C≡C-Ph H H 1-731 H H Me Me 2 —C≡C-Ph H H 1-732 Me H H Me 2—C≡C-Ph H H 1-733 CO₂Me H H Me 2 —C≡C-Ph H H 1-734 H H H Me 2—C≡C-(4-F-Ph) H H 1-735 H H H Me 2 —C≡C-(4-Me-Ph) H H 1-736 H H H Me 2—C≡C-(4-Pr-Ph) H H 1-737 H H H Me 2 —C≡C-(4-Bu-Ph) H H 1-738 H H H Me 2—C≡C-(4-MeO-Ph) H H 1-739 H H H Me 2 —C≡C-(4-EtO-Ph) H H 1-740 H H H Me2 —C≡C-(4-PrO-Ph) H H 1-741 H H H Me 2 —C≡C-(4-cHx-Ph) H H 1-742 H H HMe 2 —C≡C-(4-Ph-Ph) H H 1-743 H H H Me 2 —C≡C—(CH₂)₂-cHx H H 1-744 H HMe Me 2 —C≡C—(CH₂)₂-cHx H H 1-745 Me H H Me 2 —C≡C—(CH₂)₂-cHx H H 1-746CO₂Me H H Me 2 —C≡C—(CH₂)₂-cHx H H 1-747 H H H Me 2—C≡C—(CH₂)₂-(4-F-cHx) H H 1-748 H H H Me 2 —C≡C—(CH₂)₂-(4-Me-cHx) H H1-749 H H H Me 2 —C≡C—(CH₂)₂-(4-Et-cHx) H H 1-750 H H H Me 2—C≡C—(CH₂)₂-(4-CF₃-cHx) H H 1-751 H H H Me 2 —C≡C—(CH₂)₂-(4-MeO-cHx) H H1-752 H H H Me 2 —C≡C—(CH₂)₂-(4-EtO-cHx) H H 1-753 H H H Me 2—C≡C—(CH₂)₂-(4-MeS-cHx) H H 1-754 H H H Me 2 —C≡C—(CH₂)₂-(4-cHx-cHx) H H1-755 H H H Me 2 —C≡C—(CH₂)₂-(4-Ph-cHx) H H 1-756 H H H Me 2—C≡C—(CH₂)₂-Ph H H 1-757 H H Me Me 2 —C≡C—(CH₂)₂-Ph H H 1-758 Me H H Me2 —C≡C—(CH₂)₂-Ph H H 1-759 CO₂Me H H Me 2 —C≡C—(CH₂)₂-Ph H H 1-760 H H HMe 2 —C≡C—(CH₂)₂-(4-F-Ph) H H 1-761 H H H Me 2 —C≡C—(CH₂)₂-(4-Me-Ph) H H1-762 H H H Me 2 —C≡C—(CH₂)₂-(4-Et-Ph) H H 1-763 H H H Me 2—C≡C—(CH₂)₂-(4-CF₃-Ph) H H 1-764 H H H Me 2 —C≡C—(CH₂)₂-(4-MeO-Ph) H H1-765 H H H Me 2 —C≡C—(CH₂)₂-(4-EtO-Ph) H H 1-766 H H H Me 2—C≡C—(CH₂)₂-(4-MeS-Ph) H H 1-767 H H H Me 2 —C≡C—(CH₂)₂-(4-cHx-Ph) H H1-768 H H H Me 2 —C≡C—(CH₂)₂-(4-Ph-Ph) H H 1-769 H H H Me 2—C≡C—(CH₂)₃-cPn H H 1-770 H H H Me 2 —C≡C—(CH₂)₃-cHx H H 1-771 H H H Me2 —C≡C—(CH₂)₃-cHx Me H 1-772 H H H Me 2 —C≡C—(CH₂)₃-cHx H Me 1-773 H H HMe 2 —C≡C—(CH₂)₃-cHx F H 1-774 H H H Me 2 —C≡C—(CH₂)₃-cHx H F 1-775 H HMe Me 2 —C≡C—(CH₂)₃-cHx H H 1-776 Me H H Me 2 —C≡C—(CH₂)₃-cHx H H 1-777CO₂Me H H Me 2 —C≡C—(CH₂)₃-cHx H H 1-778 H H H Me 2—C≡C—(CH₂)₃-(3-F-cHx) H H 1-779 H H H Me 2 —C≡C—(CH₂)₃-(4-F-cHx) H H1-780 H H H Me 2 —C≡C—(CH₂)₃-(4-Cl-cHx) H H 1-781 H H H Me 2—C≡C—(CH₂)₃-(4-Br-cHx) H H 1-782 H H H Me 2 —C≡C—(CH₂)₃-(3-Me-cHx) H H1-783 H H H Me 2 —C≡C—(CH₂)₃-(4-Me-cHx) H H 1-784 H H H Me 2—C≡C—(CH₂)₃-(3-Et-cHx) H H 1-785 H H H Me 2 —C≡C—(CH₂)₃-(4-Et-cHx) H H1-786 H H H Me 2 —C≡C—(CH₂)₃-(3-Pr-cHx) H H 1-787 H H H Me 2—C≡C—(CH₂)₃-(4-Pr-cHx) H H 1-788 H H H Me 2 —C≡C—(CH₂)₃-(4-iPr-cHx) H H1-789 H H H Me 2 —C≡C—(CH₂)₃-(3-Bu-cHx) H H 1-790 H H H Me 2—C≡C—(CH₂)₃-(4-Bu-cHx) H H 1-791 H H H Me 2 —C≡C—(CH₂)₃-(3-CF₃-cHx) H H1-792 H H H Me 2 —C≡C—(CH₂)₃-(4-CF₃-cHx) H H 1-793 H H H Me 2—C≡C—(CH₂)₃-(3-MeO-cHx) H H 1-794 H H H Me 2 —C≡C—(CH₂)₃-(4-MeO-cHx) H H1-795 H H H Me 2 —C≡C—(CH₂)₃-(3-EtO-cHx) H H 1-796 H H H Me 2—C≡C—(CH₂)₃-(4-EtO-cHx) H H 1-797 H H H Me 2 —C≡C—(CH₂)₃-(3-PrO-cHx) H H1-798 H H H Me 2 —C≡C—(CH₂)₃-(4-PrO-cHx) H H 1-799 H H H Me 2—C≡C—(CH₂)₃-(3-iPrO-cHx) H H 1-800 H H H Me 2 —C≡C—(CH₂)₃-(4-iPrO-cHx) HH 1-801 H H H Me 2 —C≡C—(CH₂)₃-[3-(2-Et-PrO)-cHx] H H 1-802 H H H Me 2—C≡C—(CH₂)₃-[4-(2-Et-PrO)-cHx] H H 1-803 H H H Me 2—C≡C—(CH₂)₃-(3-iBuO-cHx) H H 1-804 H H H Me 2 —C≡C—(CH₂)₃-(4-iBuO-cHx) HH 1-805 H H H Me 2 —C≡C—(CH₂)₃-(3-MeS-cHx) H H 1-806 H H H Me 2—C≡C—(CH₂)₃-(4-MeS-cHx) H H 1-807 H H H Me 2 —C≡C—(CH₂)₃-(3-EtS-cHx) H H1-808 H H H Me 2 —C≡C—(CH₂)₃-(4-EtS-cHx) H H 1-809 H H H Me 2—C≡C—(CH₂)₃-(3-PrS-cHx) H H 1-810 H H H Me 2 —C≡C—(CH₂)₃-(4-PrS-cHx) H H1-811 H H H Me 2 —C≡C—(CH₂)₃-(3-iPrS-cHx) H H 1-812 H H H Me 2—C≡C—(CH₂)₃-(4-iPrS-cHx) H H 1-813 H H H Me 2—C≡C—(CH₂)₃-[3-(2-Et-PrS)-cHx] H H 1-814 H H H Me 2—C≡C—(CH₂)₃-[4-(2-Et-PrS)-cHx] H H 1-815 H H H Me 2—C≡C—(CH₂)₃-(3-iBuS-cHx) H H 1-816 H H H Me 2 —C≡C—(CH₂)₃-(4-iBuS-cHx) HH 1-817 H H H Me 2 —C≡C—(CH₂)₃-(3-cHx-cHx) H H 1-818 H H H Me 2—C≡C—(CH₂)₃-(4-cHx-cHx) H H 1-819 H H H Me 2 —C≡C—(CH₂)₃-(3-Ph-cHx) H H1-820 H H H Me 2 —C≡C—(CH₂)₃-(4-Ph-cHx) H H 1-821 H H H Me 2—C≡C—(CH₂)₃-(2,4-diMe-cHx) H H 1-822 H H H Me 2—C≡C—(CH₂)₃-(3,4-diMe-cHx) H H 1-823 H H H Me 2—C≡C—(CH₂)₃-(3,5-diMe-cHx) H H 1-824 H H H Me 2 —C≡C—(CH₂)₃-Ph H H 1-825H H H Me 2 —C≡C—(CH₂)₃-Ph Me H 1-826 H H H Me 2 —C≡C—(CH₂)₃-Ph H Me1-827 H H H Me 2 —C≡C—(CH₂)₃-Ph F H 1-828 H H H Me 2 —C≡C—(CH₂)₃-Ph H F1-829 H H Me Me 2 —C≡C—(CH₂)₃-Ph H H 1-830 Me H H Me 2 —C≡C—(CH₂)₃-Ph HH 1-831 CO₂Me H H Me 2 —C≡C—(CH₂)₃-Ph H H 1-832 H H H Me 2—C≡C—(CH₂)₃-(3-F-Ph) H H 1-833 H H H Me 2 —C≡C—(CH₂)₃-(4-F-Ph) H H 1-834H H H Me 2 —C≡C—(CH₂)₃-(4-Cl-Ph) H H 1-835 H H H Me 2—C≡C—(CH₂)₃-(4-Br-Ph) H H 1-836 H H H Me 2 —C≡C—(CH₂)₃-(3-Me-Ph) H H1-837 H H H Me 2 —C≡C—(CH₂)₃-(4-Me-Ph) H H 1-838 H H H Me 2—C≡C—(CH₂)₃-(3-Et-Ph) H H 1-839 H H H Me 2 —C≡C—(CH₂)₃-(4-Et-Ph) H H1-840 H H H Me 2 —C≡C—(CH₂)₃-(3-Pr-Ph) H H 1-841 H H H Me 2—C≡C—(CH₂)₃-(4-Pr-Ph) H H 1-842 H H H Me 2 —C≡C—(CH₂)₃-(3-iPr-Ph) H H1-843 H H H Me 2 —C≡C—(CH₂)₃-(4-iPr-Ph) H H 1-844 H H H Me 2—C≡C—(CH₂)₃-(3-Bu-Ph) H H 1-845 H H H Me 2 —C≡C—(CH₂)₃-(4-Bu-Ph) H H1-846 H H H Me 2 —C≡C—(CH₂)₃-(3-CF₃-Ph) H H 1-847 H H H Me 2—C≡C—(CH₂)₃-(4-CF₃-Ph) H H 1-848 H H H Me 2 —C≡C—(CH₂)₃-(3-MeO-Ph) H H1-849 H H H Me 2 —C≡C—(CH₂)₃-(4-MeO-Ph) H H 1-850 H H H Me 2—C≡C—(CH₂)₃-(3-EtO-Ph) H H 1-851 H H H Me 2 —C≡C—(CH₂)₃-(4-EtO-Ph) H H1-852 H H H Me 2 —C≡C—(CH₂)₃-(3-PrO-Ph) H H 1-853 H H H Me 2—C≡C—(CH₂)₃-(4-PrO-Ph) H H 1-854 H H H Me 2 —C≡C—(CH₂)₃-(3-iPrO-Ph) H H1-855 H H H Me 2 —C≡C—(CH₂)₃-(4-iPrO-Ph) H H 1-856 H H H Me 2—C≡C—(CH₂)₃-[3-(2-Et-PrO)-Ph] H H 1-857 H H H Me 2—C≡C—(CH₂)₃-[4-(2-Et-PrO)-Ph] H H 1-858 H H H Me 2—C≡C—(CH₂)₃-(3-iBuO-Ph) H H 1-859 H H H Me 2 —C≡C—(CH₂)₃-(4-iBuO-Ph) H H1-860 H H H Me 2 —C≡C—(CH₂)₃-(3-MeS-Ph) H H 1-861 H H H Me 2—C≡C—(CH₂)₃-(4-MeS-Ph) H H 1-862 H H H Me 2 —C≡C—(CH₂)₃-(3-EtS-Ph) H H1-863 H H H Me 2 —C≡C—(CH₂)₃-(4-EtS-Ph) H H 1-864 H H H Me 2—C≡C—(CH₂)₃-(3-PrS-Ph) H H 1-865 H H H Me 2 —C≡C—(CH₂)₃-(4-PrS-Ph) H H1-866 H H H Me 2 —C≡C—(CH₂)₃-(3-iPrS-Ph) H H 1-867 H H H Me 2—C≡C—(CH₂)₃-(4-iPrS-Ph) H H 1-868 H H H Me 2—C≡C—(CH₂)₃-[3-(2-Et-PrS)-Ph] H H 1-869 H H H Me 2—C≡C—(CH₂)₃-[4-(2-Et-PrS)-Ph] H H 1-870 H H H Me 2—C≡C—(CH₂)₃-(3-iBuS-Ph) H H 1-871 H H H Me 2 —C≡C—(CH₂)₃-(4-iBuS-Ph) H H1-872 H H H Me 2 —C≡C—(CH₂)₃-(3-cHx-Ph) H H 1-873 H H H Me 2—C≡C—(CH₂)₃-(4-cHx-Ph) H H 1-874 H H H Me 2 —C≡C—(CH₂)₃-(3-Ph-Ph) H H1-875 H H H Me 2 —C≡C—(CH₂)₃-(4-Ph-Ph) H H 1-876 H H H Me 2—C≡C—(CH₂)₃-(2,4-diMe-Ph) H H 1-877 H H H Me 2 —C≡C—(CH₂)₃-(3,4-diMe-Ph)H H 1-878 H H H Me 2 —C≡C—(CH₂)₃-(3,5-diMe-Ph) H H 1-879 H H H Me 2—C≡C—(CH₂)₃-Np(1) H H 1-880 H H H Me 2 —C≡C—(CH₂)₃-Np(2) H H 1-881 H H HMe 2 —C≡C—(CH₂)₄-cPn H H 1-882 H H H Me 2 —C≡C—(CH₂)₄-cHx H H 1-883 H HH Me 2 —C≡C—(CH₂)₄-cHx Me H 1-884 H H H Me 2 —C≡C—(CH₂)₄-cHx H Me 1-885H H H Me 2 —C≡C—(CH₂)₄-cHx F H 1-886 H H H Me 2 —C≡C—(CH₂)₄-cHx H F1-887 H H Me Me 2 —C≡C—(CH₂)₄-cHx H H 1-888 Me H H Me 2 —C≡C—(CH₂)₄-cHxH H 1-889 CO₂Me H H Me 2 —C≡C—(CH₂)₄-cHx H H 1-890 H H H Me 2—C≡C—(CH₂)₄-(3-F-cHx) H H 1-891 H H H Me 2 —C≡C—(CH₂)₄-(4-F-cHx) H H1-892 H H H Me 2 —C≡C—(CH₂)₄-(4-Cl-cHx) H H 1-893 H H H Me 2—C≡C—(CH₂)₄-(4-Br-cHx) H H 1-894 H H H Me 2 —C≡C—(CH₂)₄-(3-Me-cHx) H H1-895 H H H Me 2 —C≡C—(CH₂)₄-(4-Me-cHx) H H 1-896 H H H Me 2—C≡C—(CH₂)₄-(3-Et-cHx) H H 1-897 H H H Me 2 —C≡C—(CH₂)₄-(4-Et-cHx) H H1-898 H H H Me 2 —C≡C—(CH₂)₄-(3-Pr-cHx) H H 1-899 H H H Me 2—C≡C—(CH₂)₄-(4-Pr-cHx) H H 1-900 H H H Me 2 —C≡C—(CH₂)₄-(4-iPr-cHx) H H1-901 H H H Me 2 —C≡C—(CH₂)₄-(3-Bu-cHx) H H 1-902 H H H Me 2—C≡C—(CH₂)₄-(4-Bu-cHx) H H 1-903 H H H Me 2 —C≡C—(CH₂)₄-(3-CF₃-cHx) H H1-904 H H H Me 2 —C≡C—(CH₂)₄-(4-CF₃-cHx) H H 1-905 H H H Me 2—C≡C—(CH₂)₄-(3-MeO-cHx) H H 1-906 H H H Me 2 —C≡C—(CH₂)₄-(4-MeO-cHx) H H1-907 H H H Me 2 —C≡C—(CH₂)₄-(3-EtO-cHx) H H 1-908 H H H Me 2—C≡C—(CH₂)₄-(4-EtO-cHx) H H 1-909 H H H Me 2 —C≡C—(CH₂)₄-(3-PrO-cHx) H H1-910 H H H Me 2 —C≡C—(CH₂)₄-(4-PrO-cHx) H H 1-911 H H H Me 2—C≡C—(CH₂)₄-(3-iPrO-cHx) H H 1-912 H H H Me 2 —C≡C—(CH₂)₄-(4-iPrO-cHx) HH 1-913 H H H Me 2 —C≡C—(CH₂)₄-[3-(2-Et-PrO)-cHx] H H 1-914 H H H Me 2—C≡C—(CH₂)₄-[4-(2-Et-PrO)-cHx] H H 1-915 H H H Me 2—C≡C—(CH₂)₄-(3-iBuO-cHx) H H 1-916 H H H Me 2 —C≡C—(CH₂)₄-(4-iBuO-cHx) HH 1-917 H H H Me 2 —C≡C—(CH₂)₄-(3-MeS-cHx) H H 1-918 H H H Me 2—C≡C—(CH₂)₄-(4-MeS-cHx) H H 1-919 H H H Me 2 —C≡C—(CH₂)₄-(3-EtS-cHx) H H1-920 H H H Me 2 —C≡C—(CH₂)₄-(4-EtS-cHx) H H 1-921 H H H Me 2—C≡C—(CH₂)₄-(3-PrS-cHx) H H 1-922 H H H Me 2 —C≡C—(CH₂)₄-(4-PrS-cHx) H H1-923 H H H Me 2 —C≡C—(CH₂)₄-(3-iPrS-cHx) H H 1-924 H H H Me 2—C≡C—(CH₂)₄-(4-iPrS-cHx) H H 1-925 H H H Me 2—C≡C—(CH₂)₄-[3-(2-Et-PrS)-cHx] H H 1-926 H H H Me 2—C≡C—(CH₂)₄-[4-(2-Et-PrS)-cHx] H H 1-927 H H H Me 2—C≡C—(CH₂)₄-(3-iBuS-cHx) H H 1-928 H H H Me 2 —C≡C—(CH₂)₄-(4-iBuS-cHx) HH 1-929 H H H Me 2 —C≡C—(CH₂)₄-(3-cHx-cHx) H H 1-930 H H H Me 2—C≡C—(CH₂)₄-(4-cHx-cHx) H H 1-931 H H H Me 2 —C≡C—(CH₂)₄-(3-Ph-cHx) H H1-932 H H H Me 2 —C≡C—(CH₂)₄-(4-Ph-cHx) H H 1-933 H H H Me 2—C≡C—(CH₂)₄-(2,4-diMe-cHx) H H 1-934 H H H Me 2—C≡C—(CH₂)₄-(3,4-diMe-cHx) H H 1-935 H H H Me 2—C≡C—(CH₂)₄-(3,5-diMe-cHx) H H 1-936 H H H Me 2 —C≡C—(CH₂)₄-Ph H H 1-937H H H Me 2 —C≡C—(CH₂)₄-Ph Me H 1-938 H H H Me 2 —C≡C—(CH₂)₄-Ph H Me1-939 H H H Me 2 —C≡C—(CH₂)₄-Ph F H 1-940 H H H Me 2 —C≡C—(CH₂)₄-Ph H F1-941 H H Me Me 2 —C≡C—(CH₂)₄-Ph H H 1-942 Me H H Me 2 —C≡C—(CH₂)₄-Ph HH 1-943 CO₂Me H H Me 2 —C≡C—(CH₂)₄-Ph H H 1-944 H H H Me 2—C≡C—(CH₂)₄-(3-F-Ph) H H 1-945 H H H Me 2 —C≡C—(CH₂)₄-(4-F-Ph) H H 1-946H H H Me 2 —C≡C—(CH₂)₄-(4-Cl-Ph) H H 1-947 H H H Me 2—C≡C—(CH₂)₄-(4-Br-Ph) H H 1-948 H H H Me 2 —C≡C—(CH₂)₄-(3-Me-Ph) H H1-949 H H H Me 2 —C≡C—(CH₂)₄-(4-Me-Ph) H H 1-950 H H H Me 2—C≡C—(CH₂)₄-(3-Et-Ph) H H 1-951 H H H Me 2 —C≡C—(CH₂)₄-(4-Et-Ph) H H1-952 H H H Me 2 —C≡C—(CH₂)₄-(3-Pr-Ph) H H 1-953 H H H Me 2—C≡C—(CH₂)₄-(4-Pr-Ph) H H 1-954 H H H Me 2 —C≡C—(CH₂)₄-(3-iPr-Ph) H H1-955 H H H Me 2 —C≡C—(CH₂)₄-(4-iPr-Ph) H H 1-956 H H H Me 2—C≡C—(CH₂)₄-(3-Bu-Ph) H H 1-957 H H H Me 2 —C≡C—(CH₂)₄-(4-Bu-Ph) H H1-958 H H H Me 2 —C≡C—(CH₂)₄-(3-CF₃-Ph) H H 1-959 H H H Me 2—C≡C—(CH₂)₄-(4-CF₃-Ph) H H 1-960 H H H Me 2 —C≡C—(CH₂)₄-(3-MeO-Ph) H H1-961 H H H Me 2 —C≡C—(CH₂)₄-(4-MeO-Ph) H H 1-962 H H H Me 2—C≡C—(CH₂)₄-(3-EtO-Ph) H H 1-963 H H H Me 2 —C≡C—(CH₂)₄-(4-EtO-Ph) H H1-964 H H H Me 2 —C≡C—(CH₂)₄-(3-PrO-Ph) H H 1-965 H H H Me 2—C≡C—(CH₂)₄-(4-PrO-Ph) H H 1-966 H H H Me 2 —C≡C—(CH₂)₄-(3-iPrOPh) H H1-967 H H H Me 2 —C≡C—(CH₂)₄-(4-iPrO-Ph) H H 1-968 H H H Me 2—C≡C—(CH₂)₄-[3-(2-Et-PrO)-Ph] H H 1-969 H H H Me 2—C≡C—(CH₂)₄-[4-(2-Et-PrO)-Ph] H H 1-970 H H H Me 2—C≡C—(CH₂)₄-(3-iBuO-Ph) H H 1-971 H H H Me 2 —C≡C—(CH₂)₄-(4-iBuO-Ph) H H1-972 H H H Me 2 —C≡C—(CH₂)₄-(3-MeS-Ph) H H 1-973 H H H Me 2—C≡C—(CH₂)₄-(4-MeS-Ph) H H 1-974 H H H Me 2 —C≡C—(CH₂)₄-(3-EtS-Ph) H H1-975 H H H Me 2 —C≡C—(CH₂)₄-(4-EtS-Ph) H H 1-976 H H H Me 2—C≡C—(CH₂)₄-(3-PrS-Ph) H H 1-977 H H H Me 2 —C≡C—(CH₂)₄-(4-PrS-Ph) H H1-978 H H H Me 2 —C≡C—(CH₂)₄-(3-iPrS-Ph) H H 1-979 H H H Me 2—C≡C—(CH₂)₄-(4-iPrS-Ph) H H 1-980 H H H Me 2—C≡C—(CH₂)₄-[3-(2-Et-PrS)-Ph] H H 1-981 H H H Me 2—C≡C—(CH₂)₄-[4-(2-Et-PrS)-Ph] H H 1-982 H H H Me 2—C≡C—(CH₂)₄-(3-iBuS-Ph) H H 1-983 H H H Me 2 —C≡C—(CH₂)₄-(4-iBuS-Ph) H H1-984 H H H Me 2 —C≡C—(CH₂)₄-(3-cHx-Ph) H H 1-985 H H H Me 2—C≡C—(CH₂)₄-(4-cHx-Ph) H H 1-986 H H H Me 2 —C≡C—(CH₂)₄-(3-Ph-Ph) H H1-987 H H H Me 2 —C≡C—(CH₂)₄-(4-Ph-Ph) H H 1-988 H H H Me 2—C≡C—(CH₂)₄-(2,4-diMe-Ph) H H 1-989 H H H Me 2 —C≡C—(CH₂)₄-(3,4-diMe-Ph)H H 1-990 H H H Me 2 —C≡C—(CH₂)₄-(3,5-diMe-Ph) H H 1-991 H H H Me 2—C≡C—(CH₂)₄-Np(1) H H 1-992 H H H Me 2 —C≡C—(CH₂)₄-Np(2) H H 1-993 H H HMe 2 —C≡C—(CH₂)₅-cHx H H 1-994 H H Me Me 2 —C≡C—(CH₂)₅-cHx H H 1-995 MeH H Me 2 —C≡C—(CH₂)₅-cHx H H 1-996 CO₂Me H H Me 2 —C≡C—(CH₂)₅-cHx H H1-997 H H H Me 2 —C≡C—(CH₂)₅-(4-F-cHx) H H 1-998 H H H Me 2—C≡C—(CH₂)₅-(4-Me-cHx) H H 1-999 H H H Me 2 —C≡C—(CH₂)₅-(4-Et-cHx) H H1-1000 H H H Me 2 —C≡C—(CH₂)₅-(4-CF₃-cHx) H H 1-1001 H H H Me 2—C≡C—(CH₂)₅-(4-MeO-cHx) H H 1-1002 H H H Me 2 —C≡C—(CH₂)₅-(4-EtO-cHx) HH 1-1003 H H H Me 2 —C≡C—(CH₂)₅-(4-MeS-cHx) H H 1-1004 H H H Me 2—C≡C—(CH₂)₅-(4-cHx-cHx) H H 1-1005 H H H Me 2 —C≡C—(CH₂)₅-(4-Ph-cHx) H H1-1006 H H H Me 2 —C≡C—(CH₂)₅-Ph H H 1-1007 H H Me Me 2 —C≡C—(CH₂)₅-Ph HH 1-1008 Me H H Me 2 —C≡C—(CH₂)₅-Ph H H 1-1009 CO₂Me H H Me 2—C≡C—(CH₂)₅-Ph H H 1-1010 H H H Me 2 —C≡C—(CH₂)₅-(4-F-Ph) H H 1-1011 H HH Me 2 —C≡C—(CH₂)₅-(4-Me-Ph) H H 1-1012 H H H Me 2 —C≡C—(CH₂)₅-(4-Et-Ph)H H 1-1013 H H H Me 2 —C≡C—(CH₂)₅-(4-CF₃-Ph) H H 1-1014 H H H Me 2—C≡C—(CH₂)₅-(4-MeO-Ph) H H 1-1015 H H H Me 2 —C≡C—(CH₂)₅-(4-EtO-Ph) H H1-1016 H H H Me 2 —C≡C—(CH₂)₅-(4-MeS-Ph) H H 1-1017 H H H Me 2—C≡C—(CH₂)₅-(4-cHx-Ph) H H 1-1018 H H H Me 2 —C≡C—(CH₂)₅-(4-Ph-Ph) H H1-1019 H H H Me 2 —C≡C—(CH₂)₆-cHx H H 1-1020 H H Me Me 2 —C≡C—(CH₂)₆-cHxH H 1-1021 Me H H Me 2 —C≡C—(CH₂)₆-cHx H H 1-1022 CO₂Me H H Me 2—C≡C—(CH₂)₆-cHx H H 1-1023 H H H Me 2 —C≡C—(CH₂)₆-(4-F-cHx) H H 1-1024 HH H Me 2 —C≡C—(CH₂)₆-(4-Me-cHx) H H 1-1025 H H H Me 2—C≡C—(CH₂)₆-(4-Et-cHx) H H 1-1026 H H H Me 2 —C≡C—(CH₂)₆-(4-CF₃-cHx) H H1-1027 H H H Me 2 —C≡C—(CH₂)₆-(4-MeO-cHx) H H 1-1028 H H H Me 2—C≡C—(CH₂)₆-(4-EtO-cHx) H H 1-1029 H H H. Me 2 —C≡C—(CH₂)₆-(4-MeS-cHx) HH 1-1030 H H H Me 2 —C≡C—(CH₂)₆-(4-cHx-cHx) H H 1-1031 H H H Me 2—C≡C—(CH₂)₆-(4-Ph-cHx) H H 1-1032 H H H Me 2 —C≡C—(CH₂)₆-Ph H H 1-1033 HH Me Me 2 —C≡C—(CH₂)₆-Ph H H 1-1034 Me H H Me 2 —C≡C—(CH₂)₆-Ph H H1-1035 CO₂Me H H Me 2 —C≡C—(CH₂)₆-Ph H H 1-1036 H H H Me 2—C≡C—(CH₂)₆-(4-F-Ph) H H 1-1037 H H H Me 2 —C≡C—(CH₂)₆-(4-Me-Ph) H H1-1038 H H H Me 2 —C≡C—(CH₂)₆-(4-Et-Ph) H H 1-1039 H H H Me 2—C≡C—(CH₂)₆-(4-CF₃-Ph) H H 1-1040 H H H Me 2 —C≡C—(CH₂)₆-(4-MeO-Ph) H H1-1041 H H H Me 2 —C≡C—(CH₂)₆-(4-EtO-Ph) H H 1-1042 H H H Me 2—C≡C—(CH₂)₆-(4-MeS-Ph) H H 1-1043 H H H Me 2 —C≡C—(CH₂)₆-(4-cHx-Ph) H H1-1044 H H H Me 2 —C≡C—(CH₂)₆-(4-Ph-Ph) H H 1-1045 H H H Me 2—C≡C—CH₂—O-cHx H H 1-1046 H H Me Me 2 —C≡C—CH₂—O-cHx H H 1-1047 Me H HMe 2 —C≡C—CH₂—O-cHx H H 1-1048 CO₂Me H H Me 2 —C≡C—CH₂—O-cHx H- H 1-1049H H H Me 2 —C≡C—CH₂—O-(4-F-cHx) H H 1-1050 H H H Me 2—C≡C—CH₂—O-(4-Me-cHx) H H 1-1051 H H H Me 2 —C≡C—CH₂—O-(4-Et-cHx) H H1-1052 H H H Me 2 —C≡C—CH₂—O-(4-CF₃-cHx) H H 1-1053 H H H Me 2—C≡C—CH₂—O-(4-MeO-cHx) H H 1-1054 H H H Me 2 —C≡C—CH₂—O-(4-EtO-cHx) H H1-1055 H H H Me 2 —C≡C—CH₂—O-(4-MeS-cHx) H H 1-1056 H H H Me 2—C≡C—CH₂—O-(4-cHx-cHx) H H 1-1057 H H H Me 2 —C≡C—CH₂—O-(4-Ph-cHx) H H1-1058 H H H Me 2 —C≡C—CH₂—O-Ph H H 1-1059 H H Me Me 2 —C≡C—CH₂—O-Ph H H1-1060 Me H H Me 2 —C≡C—CH₂—O-Ph H H 1-1061 CO₂Me H H Me 2 —C≡C—CH₂—O-PhH H 1-1062 H H H Me 2 —C≡C—CH₂—O-(4-F-Ph) H H 1-1063 H H H Me 2—C≡C—CH₂—O-(4-Me-Ph) H H 1-1064 H H H Me 2 —C≡C—CH₂—O-(4-Et-Ph) H H1-1065 H H H Me 2 —C≡C—CH₂—O-(4-CF₃-Ph) H H 1-1066 H H H Me 2—C≡C—CH₂—O-(4-MeO-Ph) H H 1-1067 H H H Me 2 —C≡C—CH₂—O-(4-EtO-Ph) H H1-1068 H H H Me 2 —C≡C—CH₂—O-(4-MeS-Ph) H H 1-1069 H H H Me 2—C≡C—CH₂—O-(4-cHx-Ph) H H 1-1070 H H H Me 2 —C≡C—CH₂—O-(4-Ph-Ph) H H1-1071 H H H Me 2 —C≡C—(CH₂)₂O-cPn H H 1-1072 H H H Me 2—C≡C—(CH₂)₂O-cHx H H 1-1073 H H H Me 2 —C≡C—(CH₂)₂O-cHx Me H 1-1074 H HH Me 2 —C≡C—(CH₂)₂O-cHx H Me 1-1075 H H H Me 2 —C≡C—(CH₂)₂O-cHx F H1-1076 H H H Me 2 —C≡C—(CH₂)₂O-cHx H F 1-1077 H H Me Me 2—C≡C—(CH₂)₂O-cHx H H 1-1078 Me H H Me 2 —C≡C—(CH₂)₂O-cHx H H 1-1079CO₂Me H H Me 2 —C≡C—(CH₂)₂O-cHx H H 1-1080 H H H Me 2—C≡C—(CH₂)₂O-(3-F-cHx) H H 1-1081 H H H Me 2 —C≡C—(CH₂)₂O-(4-F-cHx) H H1-1082 H H H Me 2 —C≡C—(CH₂)₂O-(4-Cl-cHx) H H 1-1083 H H H Me 2—C≡C—(CH₂)₂O-(4-Br-cHx) H H 1-1084 H H H Me 2 —C≡C—(CH₂)₂O-(3-Me-cHx) HH 1-1085 H H H Me 2 —C≡C—(CH₂)₂O-(4-Me-cHx) H H 1-1086 H H H Me 2—C≡C—(CH₂)₂O-(3-Et-cHx) H H 1-1087 H H H Me 2 —C≡C—(CH₂)₂O-(4-Et-cHx) HH 1-1088 H H H Me 2 —C≡C—(CH₂)₂O-(3-Pr-cHx) H H 1-1089 H H H Me 2—C≡C—(CH₂)₂O-(4-Pr-cHx) H H 1-1090 H H H Me 2 —C≡C—(CH₂)₂O-(4-iPr-cHx) HH 1-1091 H H H Me 2 —C≡C—(CH₂)₂O-(3-Bu-cHx) H H 1-1092 H H H Me 2—C≡C—(CH₂)₂O-(4-Bu-cHx) H H 1-1093 H H H Me 2 —C≡C—(CH₂)₂O-(3-CF₃-cHx) HH 1-1094 H H H Me 2 —C≡C—(CH₂)₂O-(4-CF₃-cHx) H H 1-1095 H H H Me 2—C≡C—(CH₂)₂O-(3-MeO-cHx) H H 1-1096 H H H Me 2 —C≡C—(CH₂)₂O-(4-MeO-cHx)H H 1-1097 H H H Me 2 —C≡C—(CH₂)₂O-(3-EtO-cHx) H H 1-1098 H H H Me 2—C≡C—(CH₂)₂O-(4-EtO-cHx) H H 1-1099 H H H Me 2 —C≡C—(CH₂)₂O-(3-PrO-cHx)H H 1-1100 H H H Me 2 —C≡C—(CH₂)₂O-(4-PrO-cHx) H H 1-1101 H H H Me 2—C≡C—(CH₂)₂O-(3-iPrO-cHx) H H 1-1102 H H H Me 2—C≡C—(CH₂)₂O-(4-iPrO-cHx) H H 1-1103 H H H Me 2—C≡C—(CH₂)₂O-[3-(2-Et-PrO)-cHz] H H 1-1104 H H H Me 2—C≡C—(CH₂)₂O-[4-(2-Et-PrO)-cHx] H H 1-1105 H H H Me 2—C≡C—(CH₂)₂O-(3-iBuO-cHx) H H 1-1106 H H H Me 2—C≡C—(CH₂)₂O-(4-iBuO-cHx) H H 1-1107 H H H Me 2 —C≡C—(CH₂)₂O-(3-MeS-cHx)H H 1-1108 H H H Me 2 —C≡C—(CH₂)₂O-(4-MeS-cHx) H H 1-1109 H H H Me 2—C≡C—(CH₂)₂O-(3-EtS-cHx) H H 1-1110 H H H Me 2 —C≡C—(CH₂)₂O-(4-EtS-cHx)H H 1-1111 H H H Me 2 —C≡C—(CH₂)₂O-(3-PrS-cHx) H H 1-1112 H H H Me 2—C≡C—(CH₂)₂O-(4-PrS-cHx) H H 1-1113 H H H Me 2 —C≡C—(CH₂)₂O-(3-iPrS-cHx)H H 1-1114 H H H Me 2 —C≡C—(CH₂)₂O-(4-iPrS-cHx) H H 1-1115 H H H Me 2—C≡C—(CH₂)₂O-[3-(2-Et-PrS)-cHx] H H 1-1116 H H H Me 2—C≡C—(CH₂)₂O-[4-(2-Et-PrS)-cHx] H H 1-1117 H H H Me 2—C≡C—(CH₂)₂O-(3-iBuS-cHx) H H 1-1118 H H H Me 2—C≡C—(CH₂)₂O-(4-iBuS-cHx) H H 1-1119 H H H Me 2 —C≡C—(CH₂)₂O-(3-cHx-cHx)H H 1-1120 H H H Me 2 —C≡C—(CH₂)₂O-(4-cHx-cHx) H H 1-1121 H H H Me 2—C≡C—(CH₂)₂O-(3-Ph-cHx) H H 1-1122 H H H Me 2 —C≡C—(CH₂)₂O-(4-Ph-cHx) HH 1-1123 H H H Me 2 —C≡C—(CH₂)₂O-(2,4-diMe-cHx) H H 1-1124 H H H Me 2—C≡C—(CH₂)₂O-(3,4-diMe-cHx) H H 1-1125 H H H Me 2—C≡C—(CH₂)₂O-(3,5-diMe-cHx) H H 1-1126 H H H Me 2 —C≡C—(CH₂)₂O-Ph H H1-1127 H H H Me 2 —C≡C—(CH₂)₂O-Ph Me H 1-1128 H H H Me 2 —C≡C—(CH₂)₂O-PhH Me 1-1129 H H H Me 2 —C≡C—(CH₂)₂O-Ph F H 1-1130 H H H Me 2—C≡C—(CH₂)₂O-Ph H F 1-1131 H H Me Me 2 —C≡C—(CH₂)₂O-Ph H H 1-1132 Me H HMe 2 —C≡C—(CH₂)₂O-Ph H H 1-1133 CO₂Me H H Me 2 —C≡C—(CH₂)₂O-Ph H H1-1134 H H H Me 2 —C≡C—(CH₂)₂O-(3-F-Ph) H H 1-1135 H H H Me 2—C≡C—(CH₂)₂O-(4-F-Ph) H H 1-1136 H H H Me 2 —C≡C—(CH₂)₂O-(4-Cl-Ph) H H1-1137 H H H Me 2 —C≡C—(CH₂)₂O-(4-Br-Ph) H H 1-1138 H H H Me 2—C≡C—(CH₂)₂O-(3-Me-Ph) H H 1-1139 H H H Me 2 —C≡C—(CH₂)₂O-(4-Me-Ph) H H1-1140 H H H Me 2 —C≡C—(CH₂)₂O-(3-Et-Ph) H H 1-1141 H H H Me 2—C≡C—(CH₂)₂O-(4-Et-Ph) H H 1-1142 H H H Me 2 —C≡C—(CH₂)₂O-(3-Pr-Ph) H H1-1143 H H H Me 2 —C≡C—(CH₂)₂O-(4-Pr-Ph) H H 1-1144 H H H Me 2—C≡C—(CH₂)₂O-(3-iPr-Ph) H H 1-1145 H H H Me 2 —C≡C—(CH₂)₂O-(4-iPr-Ph) HH 1-1146 H H H Me 2 —C≡C—(CH₂)₂O-(3-Bu-Ph) H H 1-1147 H H H Me 2—C≡C—(CH₂)₂O-(4-Bu-Ph) H H 1-1148 H H H Me 2 —C≡C—(CH₂)₂O-(3-CF₃-Ph) H H1-1149 H H H Me 2 —C≡C—(CH₂)₂O-(4-CF₃-Ph) H H 1-1150 H H H Me 2—C≡C—(CH₂)₂O-(3-MeO-Ph) H H 1-1151 H H H Me 2 —C≡C—(CH₂)₂O-(4-MeO-Ph) HH 1-1152 H H H Me 2 —C≡C—(CH₂)₂O-(3-EtO-Ph) H H 1-1153 H H H Me 2—C≡C—(CH₂)₂O-(4-EtO-Ph) H H 1-1154 H H H Me 2 —C≡C—(CH₂)₂O-(3-PrO-Ph) HH 1-1155 H H H Me 2 —C≡C—(CH₂)₂O-(4-PrO-Ph) H H 1-1156 H H H Me 2—C≡C—(CH₂)₂O-(3-iPrO-Ph) H H 1-1157 H H H Me 2 —C≡C—(CH₂)₂O-(4-iPrO-Ph)H H 1-1158 H H H Me 2 —C≡C—(CH₂)₂O-[3-(2-Et-PrO)-Ph] H H 1-1159 H H H Me2 —C≡C—(CH₂)₂O-[4-(2-Et-PrO)-Ph] H H 1-1160 H H H Me 2—C≡C—(CH₂)₂O-(3-iBuO-Ph) H H 1-1161 H H H Me 2 —C≡C—(CH₂)₂O-(4-iBuO-Ph)H H 1-1162 H H H Me 2 —C≡C—(CH₂)₂O-(3-MeS-Ph) H H 1-1163 H H H Me 2—C≡C—(CH₂)₂O-(4-MeS-Ph) H H 1-1164 H H H Me 2 —C≡C—(CH₂)₂O-(3-EtS-Ph) HH 1-1165 H H H Me 2 —C≡C—(CH₂)₂O-(4-EtS-Ph) H H 1-1166 H H H Me 2—C≡C—(CH₂)₂O-(3-PrS-Ph) H H 1-1167 H H H Me 2 —C≡C—(CH₂)₂O-(4-PrS-Ph) HH 1-1168 H H H Me 2 —C≡C—(CH₂)₂O-(3-iPrS-Ph) H H 1-1169 H H H Me 2—C≡C—(CH₂)₂O-(4-iPrS-Ph) H H 1-1170 H H H Me 2—C≡C—(CH₂)₂O-[3-(2-Et-PrS)-Ph] H H 1-1171 H H H Me 2—C≡C—(CH₂)₂O-[4-(2-Et-PrS)-Ph] H H 1-1172 H H H Me 2—C≡C—(CH₂)₂O-(3-iBuS-Ph) H H 1-1173 H H H Me 2 —C≡C—(CH₂)₂O-(4-iBuS -Ph)H H 1-1174 H H H Me 2 —C≡C—(CH₂)₂O-(3-cHx-Ph) H H 1-1175 H H H Me 2—C≡C—(CH₂)₂O-(4-cHx-Ph) H H 1-1176 H H H Me 2 —C≡C—(CH₂)₂O-(3-Ph-Ph) H H1-1177 H H H Me 2 —C≡C—(CH₂)₂O-(4-Ph-Ph) H H 1-1178 H H H Me 2—C≡C—(CH₂)₂O-(2,4-diMe-Ph) H H 1-1179 H H H Me 2—C≡C—(CH₂)₂O-(3,4-diMe-Ph) H H 1-1180 H H H Me 2—C≡C—(CH₂)₂O-(3,5-diMe-Ph) H H 1-1181 H H H Me 2 —C≡C—(CH₂)₃O-cHx H H1-1182 H H H Me 2 —C≡C—(CH₂)₃O-Ph H H 1-1183 H H H Me 2 —C≡C—(CH₂)₄O-cHxH H 1-1184 H H H Me 2 —C≡C—(CH₂)₄O-Ph H H 1-1185 H H H Me 2—C≡C—CH₂—OCH₂-cHx H H 1-1186 H H Me Me 2 —C≡C—CH₂—OCH₂-cHx H H 1-1187 MeH H Me 2 —C≡C—CH₂—OCH₂-cHx H H 1-1188 CO₂Me H H Me 2 —C≡C—CH₂—OCH₂-cHx HH 1-1189 H H H Me 2 —C≡C—CH₂—OCH₂-(4-F-cHx) H H 1-1190 H H H Me 2—C≡C—CH₂—OCH₂-(4-Me-cHx) H H 1-1191 H H H Me 2 —C≡C—CH₂—OCH₂-(4-Et-cHx)H H 1-1192 H H H Me 2 —C≡C—CH₂—OCH₂-(4-CF₃-cHx) H H 1-1193 H H H Me 2—C≡C—CH₂—OCH₂-(4-MeO-cHx) H H 1-1194 H H H Me 2—C≡C—CH₂—OCH₂-(4-EtO-cHx) H H 1-1195 H H H Me 2—C≡C—CH₂—OCH₂-(4-MeS-cHx) H H 1-1196 H H H Me 2—C≡C—CH₂—OCH₂-(4-cHx-cHx) H H 1-1197 H H H Me 2 —C≡C—CH₂—OCH₂-(4-Ph-cHx)H H 1-1198 H H H Me 2 —C≡C—CH₂—OCH₂-Ph H H 1-1199 H H Me Me 2—C≡C—CH₂—OCH₂-Ph H H 1-1200 Me H H Me 2 —C≡C—CH₂—OCH₂-Ph H H 1-1201CO₂Me H H Me 2 —C≡C—CH₂—OCH₂-Ph H H 1-1202 H H H Me 2—C≡C—CH₂—OCH₂-(4-F-Ph) H H 1-1203 H H H Me 2 —C≡C—CH₂—OCH₂-(4-Me-Ph) H H1-1204 H H H Me 2 —C≡C—CH₂—OCH₂-(4-Et-Ph) H H 1-1205 H H H Me 2—C≡C—CH₂—OCH₂-(4-CF₃-Ph) H H 1-1206 H H H Me 2 —C≡C—CH₂—OCH₂-(4-MeO-Ph)H H 1-1207 H H H Me 2 —C≡C—CH₂—OCH₂-(4-EtO-Ph) H H 1-1208 H H H Me 2—C≡C—CH₂—OCH₂-(4-MeS-Ph) H H 1-1209 H H H Me 2 —C≡C—CH₂—OCH₂-(4-cHx-Ph)H H 1-1210 H H H Me 2 —C≡C—CH₂—OCH₂-(4-Ph-Ph) H H 1-1211 H H H Me 2—C≡C—(CH₂)₂—OCH₂-cPn H H 1-1212 H H H Me 2 —C≡C—(CH₂)₂—OCH₂-cHx H H1-1213 H H H Me 2 —C≡C—(CH₂)₂—OCH₂-cHx Me H 1-1214 H H H Me 2—C≡C—(CH₂)₂—OCH₂-cHx H Me 1-1215 H H H Me 2 —C≡C—(CH₂)₂—OCH₂-cHx F H1-1216 H H H Me 2 —C≡C—(CH₂)₂—OCH₂-cHx H F 1-1217 H H Me Me 2—C≡C—(CH₂)₂—OCH₂—CH₂-cHx H H 1-1218 Me H H Me 2 —C≡C—(CH₂)₂—OCH₂-cHx H H1-1219 CO₂Me H H Me 2 —C≡C—(CH₂)₂—OCH₂-cHx H H 1-1220 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-F-cHx) H H 1-1221 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-F-cHx) H H 1-1222 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-Cl-cHx) H H 1-1223 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-Br-cHx) H H 1-1224 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-Me-cHx) H H 1-1225 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-Me-cHx) H H 1-1226 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-Et-cHx) H H 1-1227 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-Et-cHx) H H 1-1228 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-Pr-cHx) H H 1-1229 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-Pr-cHx) H H 1-1230 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-iPr-cHx) H H 1-1231 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-Bu-cHx) H H 1-1232 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-Bu-cHx) H H 1-1233 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-CF₃-cHx) H H 1-1234 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-CF₃-cHx) H H 1-1235 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-MeO-cHx) H H 1-1236 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-MeO-cHx) H H 1-1237 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-EtO-cHx) H H 1-1238 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-EtO-cHx) H H 1-1239 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-PrO-cHx) H H 1-1240 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-PrO-cHx) H H 1-1241 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-iPrO-cHx) H H 1-1242 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-iPrO-cHx) H H 1-1243 H H H Me 2—C≡C—(CH₂)₂—OCH₂-[3-(2-Et-PrO)cHx] H H 1-1244 H H H Me 2—C≡C—(CH₂)₂—OCH₂-[4-(2-Et-PrO)cHx] H H 1-1245 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-iBuO-cHx) H H 1-1246 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-iBuO-cHx) H H 1-1247 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-MeS-cHx) H H 1-1248 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-MeS-cHx) H H 1-1249 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-EtS-cHx) H H 1-1250 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-EtS-cHx) H H 1-1251 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-PrS-cHx) H H 1-1252 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-PrS-cHx) H H 1-1253 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-iPrS-cHx) H H 1-1254 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-iPrS-cHx) H H 1-1255 H H H Me 2—C≡C—(CH₂)₂—OCH₂-[3-(2-Et-PrS)cHx] H H 1-1256 H H H Me 2—C≡C—(CH₂)₂—OCH₂-[4-(2-Et-PrS)cHx] H H 1-1257 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-iBuS-cHx) H H 1-1258 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-iBuS-cHx) H H 1-1259 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-cHx-cHx) H H 1-1260 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-cHx-cHx) H H 1-1261 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-Ph-cHx) H H 1-1262 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-Ph-cHx) H H 1-1263 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(2,4-diMe-cHx) H H 1-1264 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3,4-diMe-cHx) H H 1-1265 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3,5-diMe-cHx) H H 1-1266 H H H Me 2—C≡C—(CH₂)₂—OCH₂-Ph H H 1-1267 H H H Me 2 —C≡C—(CH₂)₂—OCH₂-Ph Me H1-1268 H H H Me 2 —C≡C—(CH₂)₂—OCH₂-Ph H Me 1-1269 H H H Me 2—C≡C—(CH₂)₂—OCH₂-Ph F H 1-1270 H H H Me 2 —C≡C—(CH₂)₂—OCH₂-Ph H F 1-1271H H Me Me 2 —C≡C—(CH₂)₂—OCH₂—CH₂-Ph H H 1-1272 Me H H Me 2—C≡C—(CH₂)₂—OCH₂-Ph H H 1-1273 CO₂Me H H Me 2 —C≡C—(CH₂)₂—OCH₂-Ph H H1-1274 H H H Me 2 —C≡C—(CH₂)₂—OCH₂-(3-F-Ph) H H 1-1275 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-F-Ph) H H 1-1276 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-Cl-Ph) H H 1-1277 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-Br-Ph) H H 1-1278 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-Me-Ph) H H 1-1279 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-Me-Ph) H H 1-1280 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-Et-Ph) H H 1-1281 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-Et-Ph) H H 1-1282 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-Pr-Ph) H H 1-1283 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-Pr-Ph) H H 1-1284 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-iPr-Ph) H H 1-1285 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-iPr-Ph) H H 1-1286 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-Bu-Ph) H H 1-1287 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-Bu-Ph) H H 1-1288 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-CF₃-Ph) H H 1-1289 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-CF₃-Ph) H H 1-1290 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-MeO-Ph) H H 1-1291 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-MeO-Ph) H H 1-1292 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-EtO-Ph) H H 1-1293 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-EtO-Ph) H H 1-1294 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-PrO-Ph) H H 1-1295 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-PrO-Ph) H H 1-1296 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-iPrO-Ph) H H 1-1297 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-iPrO-Ph) H H 1-1298 H H H Me 2—C≡C—(CH₂)₂—OCH₂-[3-(2-Et-PrO)Ph] H H 1-1299 H H H Me 2—C≡C—(CH₂)₂—OCH₂-[4-(2-Et-PrO)Ph] H H 1-1300 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-iBuO-Ph) H H 1-1301 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-iBuO-Ph) H H 1-1302 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-MeS-Ph) H H 1-1303 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-MeS-Ph) H H 1-1304 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-EtS-Ph) H H 1-1305 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-EtS-Ph) H H 1-1306 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-PrS-Ph) H H 1-1307 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-PrS-Ph) H H 1-1308 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-iPrS-Ph) H H 1-1309 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-iPrS-Ph) H H 1-1310 H H H Me 2—C≡C—(CH₂)₂—OCH₂-[3-(2-Et-PrS)Ph] H H 1-1311 H H H Me 2—C≡C—(CH₂)₂—OCH₂-[4-(2-Et-PrS)Ph] H H 1-1312 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-iBuS-Ph) H H 1-1313 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-iBuS-Ph) H H 1-1314 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-cHx-Ph) H H 1-1315 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-cHx-Ph) H H 1-1316 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3-Ph-Ph) H H 1-1317 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(4-Ph-Ph) H H 1-1318 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(2,4-diMe-Ph) H H 1-1319 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3,4-diMe-Ph) H H 1-1320 H H H Me 2—C≡C—(CH₂)₂—OCH₂-(3,5-diMe-Ph) H H 1-1321 H H H Me 2—C≡C—(CH₂)₃—OCH₂-cHx H H 1-1322 H H H Me 2 —C≡C—(CH₂)₃—OCH₂-Ph H H1-1323 H H H Me 2 —C≡C—(CH₂)₄—OCH₂-cHx H H 1-1324 H H H Me 2—C≡C—(CH₂)₄—OCH₂-Ph H H 1-1325 H H H Me 2 —CO—CH₂-(4-cHx-Ph) H H 1-1326H H H Me 2 —CO—CH₂-(4-Ph-Ph) H H 1-1327 H H H Me 2 —CO—(CH₂)₂-cHx H H1-1328 H H H Me 2 —CO—(CH₂)₂-Ph H H 1-1329 H H H Me 2 —CO—(CH₂)₃-cHx H H1-1330 H H H Me 2 —CO—(CH₂)₃-Ph H H 1-1331 H H H Me 2 —CO—(CH₂)₄-cHx H H1-1332 H H Me Me 2 —CO—(CH₂)₄-cHx H H 1-1333 Me H H Me 2 —CO—(CH₂)₄-cHxH H 1-1334 CO₂Me H H Me 2 —CO—(CH₂)₄-cHx H H 1-1335 H H H Me 2—CO—(CH₂)₄-(4-F-cHx) H H 1-1336 H H H Me 2 —CO—(CH₂)₄-(4-Me-cHx) H H1-1337 H H H Me 2 —CO—(CH₂)₄-(4-Et-cHx) H H 1-1338 H H H Me 2—CO—(CH₂)₄-(4-CF₃-cHx) H H 1-1339 H H H Me 2 —CO—(CH₂)₄-(4-MeO-cHx) H H1-1340 H H H Me 2 —CO—(CH₂)₄-(4-EtO-cHx) H H 1-1341 H H H Me 2—CO—(CH₂)₄-(4-MeS-cHx) H H 1-1342 H H H Me 2 —CO—(CH₂)₄-(4-cHx-cHx) H H1-1343 H H H Me 2 —CO—(CH₂)₄-(4-Ph-cHx) H H 1-1344 H H H Me 2—CO—(CH₂)₄-Ph H H 1-1345 H H Me Me 2 —CO—(CH₂)₄-Ph H H 1-1346 Me H H Me2 —CO—(CH₂)₄-Ph H H 1-1347 CO₂Me H H Me 2 —CO—(CH₂)₄-Ph H H 1-1348 H H HMe 2 —CO—(CH₂)₄-(4-F-Ph) H H 1-1349 H H H Me 2 —CO—(CH₂)₄-(4-Me-Ph) H H1-1350 H H H Me 2 —CO—(CH₂)₄-(4-Et-Ph) H H 1-1351 H H H Me 2—CO—(CH₂)₄-(4-CF₃-Ph) H H 1-1352 H H H Me 2 —CO—(CH₂)₄-(4-MeO-Ph) H H1-1353 H H H Me 2 —CO—(CH₂)₄-(4-EtO-Ph) H H 1-1354 H H H Me 2—CO—(CH₂)₄-(4-MeS-Ph) H H 1-1355 H H H Me 2 —CO—(CH₂)₄-(4-cHx-Ph) H H1-1356 H H H Me 2 —CO—(CH₂)₄-(4-Ph-Ph) H H 1-1357 H H H Me 2—CO—(CH₂)₅-cHx H H 1-1358 H H Me Me 2 —CO—(CH₂)₅-cHx H H 1-1359 Me H HMe 2 —CO—(CH₂)₅-cHx H H 1-1360 CO₂Me H H Me 2 —CO—(CH₂)₅-cHx H H 1-1361H H H Me 2 —CO—(CH₂)₅-(4-F-cHx) H H 1-1362 H H H Me 2—CO—(CH₂)₅-(4-Me-cHx) H H 1-1363 H H H Me 2 —CO—(CH₂)₅-(4-Et-cHx) H H1-1364 H H H Me 2 —CO—(CH₂)₅-(4-CF₃-cHx) H H 1-1365 H H H Me 2—CO—(CH₂)₅-(4-MeO-cHx) H H 1-1366 H H H Me 2 —CO—(CH₂)₅-(4-EtO-cHx) H H1-1367 H H H Me 2 —CO—(CH₂)₅-(4-MeS-cHx) H H 1-1368 H H H Me 2—CO—(CH₂)₅-(4-cHx-cHx) H H 1-1369 H H H Me 2 —CO—(CH₂)₅-(4-Ph-cHx) H H1-1370 H H H Me 2 —CO—(CH₂)₅-Ph H H 1-1371 H H Me Me 2 —CO—(CH₂)₅-Ph H H1-1372 Me H H Me 2 —CO—(CH₂)₅-Ph H H 1-1373 CO₂Me H H Me 2 —CO—(CH₂)₅-PhH H 1-1374 H H H Me 2 —CO—(CH₂)₅-(4-F-Ph) H H 1-1375 H H H Me 2—CO—(CH₂)₅-(4-Me-Ph) H H 1-1376 H H H Me 2 —CO—(CH₂)₅-(4-Et-Ph) H H1-1377 H H H Me 2 —CO—(CH₂)₅-(4-CF₃-Ph) H H 1-1378 H H H Me 2—CO—(CH₂)₅-(4-MeO-Ph) H H 1-1379 H H H Me 2 —CO—(CH₂)₅-(4-EtO-Ph) H H1-1380 H H H Me 2 —CO—(CH₂)₅-(4-MeS-Ph) H H 1-1381 H H H Me 2—CO—(CH₂)₅-(4-cHx-Ph) H H 1-1382 H H H Me 2 —CO—(CH₂)₅-(4-Ph-Ph) H H1-1383 H H H Me 2 —CO—(CH₂)₆-cHx H H 1-1384 H H H Me 2 —CO—(CH₂)₆-Ph H H1-1385 H H H Me 2 —CO—(CH₂)₇-cHx H H 1-1386 H H H Me 2 —CO—(CH₂)₇-Ph H H1-1387 H H H Me 2 —CO—(CH₂)₂—O-cHx H H 1-1388 H H Me Me 2—CO—(CH₂)₂—O-cHx H H 1-1389 Me H H Me 2 —CO—(CH₂)₂—O-cHx H H 1-1390CO₂Me H H Me 2 —CO—(CH₂)₂—O-cHx H H 1-1391 H H H Me 2—CO—(CH₂)₂—O-(4-F-cHx) H H 1-1392 H H H Me 2 —CO—(CH₂)₂—O-(4-Me-cHx) H H1-1393 H H H Me 2 —CO—(CH₂)₂—O-(4-Et-cHx) H H 1-1394 H H H Me 2—CO—(CH₂)₂—O-(4-CF₃-cHx) H H 1-1395 H H H Me 2 —CO—(CH₂)₂—O-(4-MeO-cHx)H H 1-1396 H H H Me 2 —CO—(CH₂)₂—O-(4-EtO-cHx) H H 1-1397 H H H Me 2—CO—(CH₂)₂—O-(4-MeS-cHx) H H 1-1398 H H H Me 2 —CO—(CH₂)₂—O-(4-cHx-cHx)H H 1-1399 H H H Me 2 —CO—(CH₂)₂—O-(4-Ph-cHx) H H 1-1400 H H H Me 2—CO—(CH₂)₂—O-Ph H H 1-1401 H H Me Me 2 —CO—(CH₂)₂—O-Ph H H 1-1402 Me H HMe 2 —CO—(CH₂)₂—O-Ph H H 1-1403 CO₂Me H H Me 2 —CO—(CH₂)₂—O-Ph H H1-1404 H H H Me 2 —CO—(CH₂)₂—O-(4-F-Ph) H H 1-1405 H H H Me 2—CO—(CH₂)₂—O-(4-Me-Ph) H H 1-1406 H H H Me 2 —CO—(CH₂)₂—O-(4-Et-Ph) H H1-1407 H H H Me 2 —CO—(CH₂)₂—O-(4-CF₃-Ph) H H 1-1408 H H H Me 2—CO—(CH₂)₂—O-(4-MeO-Ph) H H 1-1409 H H H Me 2 —CO—(CH₂)₂—O-(4-EtO-Ph) HH 1-1410 H H H Me 2 —CO—(CH₂)₂—O-(4-MeS-Ph) H H 1-1411 H H H Me 2—CO—(CH₂)₂—O-(4-cHx-Ph) H H 1-1412 H H H Me 2 —CO—(CH₂)₂—O-(4-Ph-Ph) H H1-1413 H H H Me 2 —CO—(CH₂)₃—O-cPn H H 1-1414 H H H Me 2—CO—(CH₂)₃—O-cHx H H 1-1415 H H H Me 2 —CO—(CH₂)₃—O-cHx Me H 1-1416 H HH Me 2 —CO—(CH₂)₃—O-cHx H Me 1-1417 H H H Me 2 —CO—(CH₂)₃—O-cHx F H1-1418 H H H Me 2 —CO—(CH₂)₃—O-cHx H F 1-1419 H H Me Me 2—CO—(CH₂)₃—O-cHx H H 1-1420 Me H H Me 2 —CO—(CH₂)₃—O-cHx H H 1-1421CO₂Me H H Me 2 —CO—(CH₂)₃—O-cHx H H 1-1422 H H H Me 2—CO—(CH₂)₃—O-(3-F-cHx) H H 1-1423 H H H Me 2 —CO—(CH₂)₃—O-(4-F-cHx) H H1-1424 H H H Me 2 —CO—(CH₂)₃—O-(4-Cl-cHx) H H 1-1425 H H H Me 2—CO—(CH₂)₃—O-(4-Br-cHx) H H 1-1426 H H H Me 2 —CO—(CH₂)₃—O-(3-Me-cHx) HH 1-1427 H H H Me 2 —CO—(CH₂)₃—O-(4-Me-cHx) H H 1-1428 H H H Me 2—CO—(CH₂)₃—O-(3-Et-cHx) H H 1-1429 H H H Me 2 —CO—(CH₂)₃—O-(4-Et-cHx) HH 1-1430 H H H Me 2 —CO—(CH₂)₃—O-(3-Pr-cHx) H H 1-1431 H H H Me 2—CO—(CH₂)₃—O-(4-Pr-cHx) H H 1-1432 H H H Me 2 —CO—(CH₂)₃—O-(4-iPr-cHx) HH 1-1433 H H H Me 2 —CO—(CH₂)₃—O-(3-Bu-cHx) H H 1-1434 H H H Me 2—CO—(CH₂)₃—O-(4-Bu-cHx) H H 1-1435 H H H Me 2 —CO—(CH₂)₃—O-(3-CF₃-cHx) HH 1-1436 H H H Me 2 —CO—(CH₂)₃—O-(4-CF₃-cHx) H H 1-1437 H H H Me 2—CO—(CH₂)₃—O-(3-MeO-cHx) H H 1-1438 H H H Me 2 —CO—(CH₂)₃—O-(4-MeO-cHx)H H 1-1439 H H H Me 2 —CO—(CH₂)₃—O-(3-EtO-cHx) H H 1-1440 H H H Me 2—CO—(CH₂)₃—O-(4-EtO-cHx) H H 1-1441 H H H Me 2 —CO—(CH₂)₃—O-(3-PrO-cHx)H H 1-1442 H H H Me 2 —CO—(CH₂)₃—O-(4-PrO-cHx) H H 1-1443 H H H Me 2—CO—(CH₂)₃—O-(3-iPrO-cHx) H H 1-1444 H H H Me 2—CO—(CH₂)₃—O-(4-iPrO-cHx) H H 1-1445 H H H Me 2—CO—(CH₂)₃—O-[3-(2-Et-PrO)cHx] H H 1-1446 H H H Me 2—CO—(CH₂)₃—O-[4-(2-Et-PrO)cHx] H H 1-1447 H H H Me 2—CO—(CH₂)₃—O-(3-iBuO-cHx) H H 1-1448 H H H Me 2—CO—(CH₂)₃—O-(4-iBuO-cHx) H H 1-1449 H H H Me 2 —CO—(CH₂)₃—O-(3-MeS-cHx)H H 1-1450 H H H Me 2 —CO—(CH₂)₃—O-(4-MeS-cHx) H H 1-1451 H H H Me 2—CO—(CH₂)₃—O-(3-EtS-cHx) H H 1-1452 H H H Me 2 —CO—(CH₂)₃—O-(4-EtS-cHx)H H 1-1453 H H H Me 2 —CO—(CH₂)₃—O-(3-PrS-cHx) H H 1-1454 H H H Me 2—CO—(CH₂)₃—O-(4-PrS-cHx) H H 1-1455 H H H Me 2 —CO—(CH₂)₃—O-(3-iPrS-cHx)H H 1-1456 H H H Me 2 —CO—(CH₂)₃—O-(4-iPrS-cHx) H H 1-1457 H H H Me 2—CO—(CH₂)₃—O-[3-(2-Et-PrS)cHx] H H 1-1458 H H H Me 2—CO—(CH₂)₃—O-[4-(2-Et-PrS)cHx] H H 1-1459 H H H Me 2—CO—(CH₂)₃—O-(3-iBuS-cHx) H H 1-1460 H H H Me 2—CO—(CH₂)₃—O-(4-iBuS-cHx) H H 1-1461 H H H Me 2 —CO—(CH₂)₃—O-(3-cHx-cHx)H H 1-1462 H H H Me 2 —CO—(CH₂)₃—O-(4-cHx-cHx) H H 1-1463 H H H Me 2—CO—(CH₂)₃—O-(3-Ph-cHx) H H 1-1464 H H H Me 2 —CO—(CH₂)₃—O-(4-Ph-cHx) HH 1-1465 H H H Me 2 —CO—(CH₂)₃—O-(2,4-diMe-cHx) H H 1-1466 H H H Me 2—CO—(CH₂)₃—O-(3,4-diMe-cHx) H H 1-1467 H H H Me 2—CO—(CH₂)₃—O-(3,5-diMe-cHx) H H 1-1468 H H H Me 2 —CO—(CH₂)₃—O-Ph H H1-1469 H H H Me 2 —CO—(CH₂)₃—O-Ph Me H 1-1470 H H H Me 2 —CO—(CH₂)₃—O-PhH Me 1-1471 H H H Me 2 —CO—(CH₂)₃—O-Ph F H 1-1472 H H H Me 2—CO—(CH₂)₃—O-Ph H F 1-1473 H H Me Me 2 —CO—(CH₂)₃—O-Ph H H 1-1474 Me H HMe 2 —CO—(CH₂)₃—O-Ph H H 1-1475 CO₂Me H H Me 2 —CO—(CH₂)₃—O-Ph H H1-1476 H H H Me 2 —CO—(CH₂)₃—O-(3-F-Ph) H H 1-1477 H H H Me 2—CO—(CH₂)₃—O-(4-F-Ph) H H 1-1478 H H H Me 2 —CO—(CH₂)₃—O-(4-Cl-Ph) H H1-1479 H H H Me 2 —CO—(CH₂)₃—O-(4-Br-Ph) H H 1-1480 H H H Me 2—CO—(CH₂)₃—O-(3-Me-Ph) H H 1-1481 H H H Me 2 —CO—(CH₂)₃—O-(4-Me-Ph) H H1-1482 H H H Me 2 —CO—(CH₂)₃—O-(3-Et-Ph) H H 1-1483 H H H Me 2—CO—(CH₂)₃—O-(4-Et-Ph) H H 1-1484 H H H Me 2 —CO—(CH₂)₃—O-(3-Pr-Ph) H H1-1485 H H H Me 2 —CO—(CH₂)₃—O-(4-Pr-Ph) H H 1-1486 H H H Me 2—CO—(CH₂)₃—O-(3-iPr-Ph) H H 1-1487 H H H Me 2 —CO—(CH₂)₃—O-(4-iPr-Ph) HH 1-1488 H H H Me 2 —CO—(CH₂)₃—O-(3-Bu-Ph) H H 1-1489 H H H Me 2—CO—(CH₂)₃—O-(4-Bu-Ph) H H 1-1490 H H H Me 2 —CO—(CH₂)₃—O-(3-CF₃-Ph) H H1-1491 H H H Me 2 —CO—(CH₂)₃—O-(4-CF₃-Ph) H H 1-1492 H H H Me 2—CO—(CH₂)₃—O-(3-MeO-Ph) H H 1-1493 H H H Me 2 —CO—(CH₂)₃—O-(4-MeO-Ph) HH 1-1494 H H H Me 2 —CO—(CH₂)₃—O-(3-EtO-Ph) H H 1-1495 H H H Me 2—CO—(CH₂)₃—O-(4-EtO-Ph) H H 1-1496 H H H Me 2 —CO—(CH₂)₃—O-(3-PrO-Ph) HH 1-1497 H H H Me 2 —CO—(CH₂)₃—O-(4-PrO-Ph) H H 1-1498 H H H Me 2—CO—(CH₂)₃—O-(3-iPrO-Ph) H H 1-1499 H H H Me 2 —CO—(CH₂)₃—O-(4-iPrO-Ph)H H 1-1500 H H H Me 2 —CO—(CH₂)₃—O-[3-(2-Et-PrO)-Ph] H H 1-1501 H H H Me2 —CO—(CH₂)₃—O-[4-(2-Et-PrO)-Ph] H H 1-1502 H H H Me 2—CO—(CH₂)₃—O-(3-iBuO-Ph) H H 1-1503 H H H Me 2 —CO—(CH₂)₃—O-(4-iBuO-Ph)H H 1-1504 H H H Me 2 —CO—(CH₂)₃—O-(3-MeS-Ph) H H 1-1505 H H H Me 2—CO—(CH₂)₃—O-(4-MeS-Ph) H H 1-1506 H H H Me 2 —CO—(CH₂)₃—O-(3-EtS-Ph) HH 1-1507 H H H Me 2 —CO—(CH₂)₃—O-(4-EtS-Ph) H H 1-1508 H H H Me 2—CO—(CH₂)₃—O-(3-PrS-Ph) H H 1-1509 H H H Me 2 —CO—(CH₂)₃—O-(4-PrS-Ph) HH 1-1510 H H H Me 2 —CO—(CH₂)₃—O-(3-iPrS-Ph) H H 1-1511 H H H Me 2—CO—(CH₂)₃—O-(4-iPrS-Ph) H H 1-1512 H H H Me 2—CO—(CH₂)₃—O-[3-(2-Et-PrS)-Ph] H H 1-1513 H H H Me 2—CO—(CH₂)₃—O-[4-(2-Et-PrS)-Ph] H H 1-1514 H H H Me 2—CO—(CH₂)₃—O-(3-iBuS-Ph) H H 1-1515 H H H Me 2 —CO—(CH₂)₃—O-(4-iBuS-Ph)H H 1-1516 H H H Me 2 —CO—(CH₂)₃—O-(3-cHx-Ph) H H 1-1517 H H H Me 2—CO—(CH₂)₃—O-(4-cHx-Ph) H H 1-1518 H H H Me 2 —CO—(CH₂)₃—O-(3-Ph-Ph) H H1-1519 H H H Me 2 —CO—(CH₂)₃—O-(4-Ph-Ph) H H 1-1520 H H H Me 2—CO—(CH₂)₃—O-(2,4-diMe-Ph) H H 1-1521 H H H Me 2—CO—(CH₂)₃—O-(3,4-diMe-Ph) H H 1-1522 H H H Me 2—CO—(CH₂)₃—O-(3,5-diMe-Ph) H H 1-1523 H H H Me 2 —CO—(CH₂)₄—O-cHx H H1-1524 H H H Me 2 —CO—(CH₂)₄—O-Ph H H 1-1525 H H H Me 2 —CO—(CH₂)₅—O-cHxH H 1-1526 H H H Me 2 —CO—(CH₂)₅—O-Ph H H 1-1527 H H H Me 2—CO—(CH₂)₂—OCH₂-cHx H H 1-1528 H H Me Me 2 —CO—(CH₂)₂—OCH₂-cHx H H1-1529 Me H H Me 2 —CO—(CH₂)₂—OCH₂-cHx H H 1-1530 CO₂Me H H Me 2—CO—(CH₂)₂—OCH₂-cHx H H 1-1531 H H H Me 2 —CO—(CH₂)₂—OCH₂-(4-F-cHx) H H1-1532 H H H Me 2 —CO—(CH₂)₂—OCH₂-(4-Me-cHx) H H 1-1533 H H H Me 2—CO—(CH₂)₂—OCH₂-(4-Et-cHx). H H 1-1534 H H H Me 2—CO—(CH₂)₂—OCH₂-(4-CF₃-cHx) H H 1-1535 H H H Me 2—CO—(CH₂)₂—OCH₂-(4-MeO-cHx) H H 1-1536 H H H Me 2—CO—(CH₂)₂—OCH₂-(4-EtO-cHx) H H 1-1537 H H H Me 2—CO—(CH₂)₂—OCH₂-(4-MeS-cHx) H H 1-1538 H H H Me 2—CO—(CH₂)₂—OCH₂-(4-cHx-cHx) H H 1-1539 H H H Me 2—CO—(CH₂)₂—OCH₂-(4-Ph-cHx) H H 1-1540 H H H Me 2 —CO—(CH₂)₂—OCH₂-Ph H H1-1541 H H Me Me 2 —CO—(CH₂)₂—OCH₂-Ph H H 1-1542 Me H H Me 2—CO—(CH₂)₂—OCH₂-Ph H H 1-1543 CO₂Me H H Me 2 —CO—(CH₂)₂—OCH₂-Ph H H1-1544 H H H Me 2 —CO—(CH₂)₂—OCH₂-(4-F-Ph) H H 1-1545 H H H Me 2—CO—(CH₂)₂—OCH₂-(4-Me-Ph) H H 1-1546 H H H Me 2—CO—(CH₂)₂—OCH₂-(4-Et-Ph) H H 1-1547 H H H Me 2—CO—(CH₂)₂—OCH₂-(4-CF₃-Ph) H H 1-1548 H H H Me 2—CO—(CH₂)₂—OCH₂-(4-MeO-Ph) H H 1-1549 H H H Me 2—CO—(CH₂)₂—OCH₂-(4-EtO-Ph) H H 1-1550 H H H Me 2—CO—(CH₂)₂—OCH₂-(4-MeS-Ph) H H 1-1551 H H H Me 2—CO—(CH₂)₂—OCH₂-(4-cHx-Ph) H H 1-1552 H H H Me 2—CO—(CH₂)₂—OCH₂-(4-Ph-Ph) H H 1-1553 H H H Me 2 —CO—(CH₂)₃—OCH₂—CH₂-cPnH H 1-1554 H H H Me 2 —CO—(CH₂)₃—OCH₂-cHx H H 1-1555 H H H Me 2—CO—(CH₂)₃—OCH₂-cHx Me H 1-1556 H H H Me 2 —CO—(CH₂)₃—OCH₂-cHx H Me1-1557 H H H Me 2 —CO—(CH₂)₃—OCH₂-cHx F H 1-1558 H H H Me 2—CO—(CH₂)₃—OCH₂-cHx H F 1-1559 H H Me Me 2 —CO—(CH₂)₃—OCH₂-cHx H H1-1560 Me H H Me 2 —CO—(CH₂)₃—OCH₂-cHx H H 1-1561 CO₂Me H H Me 2—CO—(CH₂)₃—OCH₂-cHx H H 1-1562 H H H Me 2 —CO—(CH₂)₃—OCH₂-(3-F-cHx) H H1-1563 H H H Me 2 —CO—(CH₂)₃—OCH₂-(4-F-cHx) H H 1-1564 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-Cl-cHx) H H 1-1565 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-Br-cHx) H H 1-1566 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-Me-cHx) H H 1-1567 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-Me-cHx) H H 1-1568 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-Et-cHx) H H 1-1569 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-Et-cHx) H H 1-1570 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-Pr-cHx) H H 1-1571 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-Pr-cHx) H H 1-1572 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-iPr-cHx) H H 1-1573 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-Bu-cHx) H H 1-1574 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-Bu-cHx) H H 1-1575 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-CF₃-cHx) H H 1-1576 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-CF₃-cHx) H H 1-1577 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-MeO-cHx) H H 1-1578 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-MeO-cHx) H H 1-1579 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-EtO-cHx) H H 1-1580 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-EtO-cHx) H H 1-1581 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-PrO-cHx) H H 1-1582 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-PrO-cHx) H H 1-1583 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-iPrO-cHx) H H 1-1584 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-iPrO-cHx) H H 1-1585 H H H Me 2—CO—(CH₂)₃—OCH₂-[3-(2-Et-PrO)cHx] H H 1-1586 H H H Me 2—CO—(CH₂)₃—OCH₂-[4-(2-Et-PrO)cHx] H H 1-1587 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-iBuO-cHx) H H 1-1588 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-iBuO-cHx) H H 1-1589 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-MeS-cHx) H H 1-1590 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-MeS-cHx) H H 1-1591 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-EtS-cHx) H H 1-1592 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-EtS-cHx) H H 1-1593 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-PrS-cHx) H H 1-1594 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-PrS-cHx) H H 1-1595 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-iPrS-cHx) H H 1-1596 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-iPrS-cHx) H H 1-1597 H H H Me 2—CO—(CH₂)₃—OCH₂-[3-(2-Et-PrS)cHx] H H 1-1598 H H H Me 2—CO—(CH₂)₃—OCH₂-[4-(2-Et-PrS)cHx] H H 1-1599 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-iBuS-cHx) H H 1-1600 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-iBuS-cHx) H H 1-1601 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-cHx-cHx) H H 1-1602 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-cHx-cHx) H H 1-1603 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-Ph-cHx) H H 1-1604 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-Ph-cHx) H H 1-1605 H H H Me 2—CO—(CH₂)₃—OCH₂-(2,4-diMe-cHx) H H 1-1606 H H H Me 2—CO—(CH₂)₃—OCH₂-(3,4-diMe-cHx) H H 1-1607 H H H Me 2—CO—(CH₂)₃—OCH₂-(3,5-diMe-cHx) H H 1-1608 H H H Me 2 —CO—(CH₂)₃—OCH₂-PhH H 1-1609 H H H Me 2 —CO—(CH₂)₃—OCH₂-Ph Me H 1-1610 H H H Me 2—CO—(CH₂)₃—OCH₂-Ph H Me 1-1611 H H H Me 2 —CO—(CH₂)₃—OCH₂-Ph F H 1-1612H H H Me 2 —CO—(CH₂)₃—OCH₂-Ph H F 1-1613 H H Me Me 2 —CO—(CH₂)₃—OCH₂-PhH H 1-1614 Me H H Me 2 —CO—(CH₂)₃—OCH₂-Ph H H 1-1615 CO₂Me H H Me 2—CO—(CH₂)₃—OCH₂-Ph H H 1-1616 H H H Me 2 —CO—(CH₂)₃—OCH₂-(3-F-Ph) H H1-1617 H H H Me 2 —CO—(CH₂)₃—OCH₂-(4-F-Ph) H H 1-1618 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-Cl-Ph) H H 1-1619 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-Br-Ph) H H 1-1620 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-Me-Ph) H H 1-1621 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-Me-Ph) H H 1-1622 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-Et-Ph) H H 1-1623 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-Et-Ph) H H 1-1624 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-Pr-Ph) H H 1-1625 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-Pr-Ph) H H 1-1626 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-iPr-Ph) H H 1-1627 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-iPr-Ph) H H 1-1628 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-Bu-Ph) H H 1-1629 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-Bu-Ph) H H 1-1630 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-CF₃-Ph) H H 1-1631 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-CF₃-Ph) H H 1-1632 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-MeO-Ph) H H 1-1633 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-MeO-Ph) H H 1-1634 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-EtO-Ph) H H 1-1635 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-EtO-Ph) H H 1-1636 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-PrO-Ph) H H 1-1637 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-PrO-Ph) H H 1-1638 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-iPrO-Ph) H H 1-1639 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-iPrO-Ph) H H 1-1640 H H H Me 2—CO—(CH₂)₃—OCH₂-[3-(2-Et-PrO)Ph] H H 1-1641 H H H Me 2—CO—(CH₂)₃—OCH₂-[4-(2-Et-PrO)Ph] H H 1-1642 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-iBuO-Ph) H H 1-1643 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-iBuO-Ph) H H 1-1644 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-MeS-Ph) H H 1-1645 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-MeS-Ph) H H 1-1646 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-EtS-Ph) H H 1-1647 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-EtS-Ph) H H 1-1648 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-PrS-Ph) H H 1-1649 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-PrS-Ph) H H 1-1650 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-iPrS-Ph) H H 1-1651 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-iPrS-Ph) H H 1-1652 H H H Me 2—CO—(CH₂)₃—OCH₂-[3-(2-Et-PrS)Ph] H H 1-1653 H H H Me 2—CO—(CH₂)₃—OCH₂-[4-(2-Et-PrS)Ph] H H 1-1654 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-iBuS-Ph) H H 1-1655 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-iBuS-Ph) H H 1-1656 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-cHx-Ph) H H 1-1657 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-cHx-Ph) H H 1-1658 H H H Me 2—CO—(CH₂)₃—OCH₂-(3-Ph-Ph) H H 1-1659 H H H Me 2—CO—(CH₂)₃—OCH₂-(4-Ph-Ph) H H 1-1660 H H H Me 2—CO—(CH₂)₃—OCH₂-(2,4-diMe-Ph) H H 1-1661 H H H Me 2—CO—(CH₂)₃—OCH₂-(3,4-diMe-Ph) H H 1-1662 H H H Me 2—CO—(CH₂)₃—OCH₂-(3,5-diMe-Ph) H H 1-1663 H H H Me 2 —CO—(CH₂)₄—OCH₂-cHxH H 1-1664 H H H Me 2 —CO—(CH₂)₄—OCH₂-Ph H H 1-1665 H H H Me 2—CO—(CH₂)₅—OCH₂-cHX H H 1-1666 H H H Me 2 —CO—(CH₂)₅—OCH₂-Ph H H 1-1667H H H Me 2 —CH(OH)—CH₂-cHx H H 1-1668 H H H Me 2 —CH(OH)—CH₂-Ph H H1-1669 H H H Me 2 —CH(OH)—(CH₂)₂-cHx H H 1-1670 H H H Me 2—CH(OH)—(CH₂)₂-Ph H H 1-1671 H H H Me 2 —CH(OH)—(CH₂)₃-cHx H H 1-1672 HH H Me 2 —CH(OH)—(CH₂)₃-Ph H H 1-1673 H H H Me 2 —CH(OH)—(CH₂)₄-cHx H H1-1674 H H Me Me 2 —CH(OH)—(CH₂)₄-cHx H H 1-1675 Me H H Me 2—CH(OH)—(CH₂)₄-cHx H H 1-1676 CO₂Me H H Me 2 —CH(OH)—(CH₂)₄-cHx H H1-1677 H H H Me 2 —CH(OH)—(CH₂)₄-(4-F-cHx) H H 1-1678 H H H Me 2—CH(OH)—(CH₂)₄-(4-Me-cHx) H H 1-1679 H H H Me 2—CH(OH)—(CH₂)₄-(4-Et-cHx) H H 1-1680 H H H Me 2—CH(OH)—(CH₂)₄-(4-CF₃-cHx) H H 1-1681 H H H Me 2—CH(OH)—(CH₂)₄-(4-MeO-cHx) H H 1-1682 H H H Me 2—CH(OH)—(CH₂)₄-(4-EtO-cHx) H H 1-1683 H H H Me 2—CH(OH)—(CH₂)₄-(4-MeS-cHx) H H 1-1684 H H H Me 2—CH(OH)—(CH₂)₄-(4-cHx-cHx) H H 1-1685 H H H Me 2—CH(OH)—(CH₂)₄-(4-Ph-cHx) H H 1-1686 H H H Me 2 —CH(OH)—(CH₂)₄-Ph H H1-1687 H H Me Me 2 —CH(OH)—(CH₂)₄-Ph H H 1-1688 Me H H Me 2—CH(OH)—(CH₂)₄-Ph H H 1-1689 CO₂Me H H Me 2 —CH(OH)—(CH₂)₄-Ph H H 1-1690H H H Me 2 —CH(OH)—(CH₂)₄-(4-F-Ph) H H 1-1691 H H H Me 2—CH(OH)—(CH₂)₄-(4-Me-Ph) H H 1-1692 H H H Me 2 —CH(OH)—(CH₂)₄-(4-Et-Ph)H H 1-1693 H H H Me 2 —CH(OH)—(CH₂)₄-(4-CF₃-Ph) H H 1-1694 H H H Me 2—CH(OH)—(CH₂)₄-(4-MeO-Ph) H H 1-1695 H H H Me 2—CH(OH)—(CH₂)₄-(4-EtO-Ph) H H 1-1696 H H H Me 2—CH(OH)—(CH₂)₄-(4-MeS-Ph) H H 1-1697 H H H Me 2—CH(OH)—(CH₂)₄-(4-cHx-Ph) H H 1-1698 H H H Me 2 —CH(OH)—(CH₂)₄-(4-Ph-Ph)H H 1-1699 H H H Me 2 —CH(OH)—(CH₂)₅-cHx H H 1-1700 H H Me Me 2—CH(OH)—(CH₂)₅-cHx H H 1-1701 Me H H Me 2 —CH(OH)—(CH₂)₅-cHx H H 1-1702CO₂Me H H Me 2 —CH(OH)—(CH₂)₅-cHx H H 1-1703 H H H Me 2—CH(OH)—(CH₂)₅-(4-F-cHx) H H 1-1704 H H H Me 2 —CH(OH)—(CH₂)₅-(4-Me-cHx)H H 1-1705 H H H Me 2 —CH(OH)—(CH₂)₅-(4-Et-cHx) H H 1-1706 H H H Me 2—CH(OH)—(CH₂)₅-(4-CF₃-cHx) H H 1-1707 H H H Me 2—CH(OH)—(CH₂)₅-(4-MeO-cHx) H H 1-1708 H H H Me 2—CH(OH)—(CH₂)₅-(4-EtO-cHx) H H 1-1709 H H H Me 2—CH(OH)—(CH₂)₅-(4-MeS-cHx) H H 1-1710 H H H Me 2—CH(OH)—(CH₂)₅-(4-cHx-cHx) H H 1-1711 H H H Me 2—CH(OH)—(CH₂)₅-(4-Ph-cHx) H H 1-1712 H H H Me 2 —CH(OH)—(CH₂)₅-Ph H H1-1713 H H Me Me 2 —CH(OH)—(CH₂)₅-Ph H H 1-1714 Me H H Me 2—CH(OH)—(CH₂)₅-Ph H H 1-1715 CO₂Me H H Me 2 —CH(OH)—(CH₂)₅-Ph H H 1-1716H H H Me 2 —CH(OH)—(CH₂)₅-(4-F-Ph) H H 1-1717 H H H Me 2—CH(OH)—(CH₂)₅-(4-Me-Ph) H H 1-1718 H H H Me 2 —CH(OH)—(CH₂)₅-(4-Et-Ph)H H 1-1719 H H H Me 2 —CH(OH)—(CH₂)₅-(4-CF₃-Ph) H H 1-1720 H H H Me 2—CH(OH)—(CH₂)₅-(4-MeO-Ph) H H 1-1721 H H H Me 2—CH(OH)—(CH₂)₅-(4-EtO-Ph) H H 1-1722 H H H Me 2—CH(OH)—(CH₂)₅-(4-MeS-Ph) H H 1-1723 H H H Me 2—CH(OH)—(CH₂)₅-(4-cHx-Ph) H H 1-1724 H H H Me 2 —CH(OH)—(CH₂)₅-(4-Ph-Ph)H H 1-1725 H H H Me 2 —CH(OH)—(CH₂)₆-cHx H H 1-1726 H H H Me 2—CH(OH)—(CH₂)₆-Ph H H 1-1727 H H H Me 2 —CH(OH)—(CH₂)₇-cHx H H 1-1728 HH H Me 2 —CH(OH)—(CH₂)₇-Ph H H 1-1729 H H H Me 2 -4-(cHx-CH₂O)Ph H H1-1730 H H Me Me 2 -4-(cHx-CH₂O)Ph H H 1-1731 Me H H Me 2-4-(cHx-CH₂O)Ph H H 1-1732 CO₂Me H H Me 2 -4-(cHx-CH₂O)Ph H H 1-1733 H HH Me 2 -4-(cHx-CH₂O)-2-F-Ph H H 1-1734 H H H Me 2 -4-(cHx-CH₂O)-3-F-Ph HH 1-1735 H H H Me 2 -4-(cHx-CH₂O)-2,3-diF-Ph H H 1-1736 H H H Me 2-4-(cHx-CH₂O)-2-Cl-Ph H H 1-1737 H H H Me 2 -4-(cHx-CH₂O)-3-Cl-Ph H H1-1738 H H H Me 2 -4-(cHx-CH₂O)-2,3-diCl-Ph H H 1-1739 H H H Me 2-4-(cHx-CH₂O)-2-Me-Ph H H 1-1740 H H H Me 2 -4-(cHx-CH₂O)-3-Me-Ph H H1-1741 H H H Me 2 -4-(cHx-CH₂O)-2,3-diMe-Ph H H 1-1742 H H H Me 2-4-[cHx-(CH₂)₂O]Ph H H 1-1743 H H H Me 2 -4-[cHx-(CH₂)₃O]Ph H H 1-1744 HH H Me 2 -(4-BzO-Ph) H H 1-1745 H H Me Me 2 -(4-BzO-Ph) H H 1-1746 Me HH Me 2 -(4-BzO-Ph) H H 1-1747 CO₂Me H H Me 2 -(4-BzO-Ph) H H 1-1748 H HH Me 2 -(4-BzO-2-F-Ph) H H 1-1749 H H H Me 2 -(4-BzO-3-F-Ph) H H 1-1750H H H Me 2 -(4-BzO-2,3-diF-Ph) H H 1-1751 H H H Me 2 -(4-BzO-2-Cl-Ph) HH 1-1752 H H H Me 2 -(4-BzO-3-Cl-Ph) H H 1-1753 H H H Me 2-(4-BzO-2,3-diCl-Ph) H H 1-1754 H H H Me 2 -(4-BzO-2-Me-Ph) H H 1-1755 HH H Me 2 -(4-BzO-3-Me-Ph) H H 1-1756 H H H Me 2 -(4-BzO-2,3-diMe-Ph) H H1-1757 H H H Me 2 -4-[Ph-(CH₂)₂O]-Ph H H 1-1758 H H H Me 2-4-[Ph-(CH₂)₃O]-Ph H H 1-1759 H H H Et 2 —(CH₂)₃-cHx H H 1-1760 H H H Et2 —(CH₂)₃-Ph H H 1-1761 H H H Et 2 —(CH₂)₄-cHx H H 1-1762 H H H Et 2—(CH₂)₄-Ph H H 1-1763 H H H Et 2 —(CH₂)₅-cPn H H 1-1764 H H H Et 2—(CH₂)₅-cHx H H 1-1765 H H H Et 2 —(CH₂)₅-cHx Me H 1-1766 H H H Et 2—(CH₂)₅-cHx H Me 1-1767 H H H Et 2 —(CH₂)₅-cHx F H 1-1768 H H H Et 2—(CH₂)₅-cHx H F 1-1769 H H Me Et 2 —(CH₂)₅-cHx H H 1-1770 Me H H Et 2—(CH₂)₅-cHx H H 1-1771 CO₂Me H H Et 2 —(CH₂)₅-cHx H H 1-1772 H H H Et 2—(CH₂)₅-(4-F-cHx) H H 1-1773 H H H Et 2 —(CH₂)₅-(4-Cl-cHx) H H 1-1774 HH H Et 2 —(CH₂)₅-(4-Br-cHx) H H 1-1775 H H H Et 2 —(CH₂)₅-(4-Me-cHx) H H1-1776 H H H Et 2 —(CH₂)₅-(4-Et-cHx) H H 1-1777 H H H Et 2—(CH₂)₅-(4-Pr-cHx) H H 1-1778 H H H Et 2 —(CH₂)₅-(4-iPr-cHx) H H 1-1779H H H Et 2 —(CH₂)₅-(4-CF₃-cHx) H H 1-1780 H H H Et 2 —(CH₂)₅-(4-MeO-cHx)H H 1-1781 H H H Et 2 —(CH₂)₅-(4-EtO-cHx) H H 1-1782 H H H Et 2—(CH₂)₅-(4-PrO-cHx) H H 1-1783 H H H Et 2 —(CH₂)₅-(4-iPrO-cHx) H H1-1784 H H H Et 2 —(CH₂)₅-(3-MeS-cHx) H H 1-1785 H H H Et 2—(CH₂)₅-(4-MeS-cHx) H H 1-1786 H H H Et 2 —(CH₂)₅-(2,4-diMe-cHx) H H1-1787 H H H Et 2 —(CH₂)₅-(3,4-diMe-cHx) H H 1-1788 H H H Et 2—(CH₂)₅-(3,5-diMe-cHx) H H 1-1789 H H H Et 2 —(CH₂)₅-Ph H H 1-1790 H H HEt 2 —(CH₂)₅-Ph Me H 1-1791 H H H Et 2 —(CH₂)₅-Ph H Me 1-1792 H H H Et 2—(CH₂)₅-Ph F H 1-1793 H H H Et 2 —(CH₂)₅-Ph H F 1-1794 H H Me Et 2—(CH₂)₅-Ph H H 1-1795 Me H H Et 2 —(CH₂)₅-Ph H H 1-1796 CO₂Me H H Et 2—(CH₂)₅-Ph H H 1-1797 H H H Et 2 —(CH₂)₅-(4-F-Ph) H H 1-1798 H H H Et 2—(CH₂)₅-(4-Cl-Ph) H H 1-1799 H H H Et 2 —(CH₂)₅-(4-Br-Ph) H H 1-1800 H HH Et 2 —(CH₂)₅-(4-Me-Ph) H H 1-1801 H H H Et 2 —(CH₂)₅-(4-Et-Ph) H H1-1802 H H H Et 2 —(CH₂)₅-(4-Pr-Ph) H H 1-1803 H H H Et 2—(CH₂)₅-(4-iPr-Ph) H H 1-1804 H H H Et 2 —(CH₂)₅-(4-Bu-Ph) H H 1-1805 HH H Et 2 —(CH₂)₅-(4-CF₃-Ph) H H 1-1806 H H H Et 2 —(CH₂)₅-(4-MeO-Ph) H H1-1807 H H H Et 2 —(CH₂)₅-(4-EtO-Ph) H H 1-1808 H H H Et 2—(CH₂)₅-(4-PrO-Ph) H H 1-1809 H H H Et 2 —(CH₂)₅-(4-iPrO-Ph) H H 1-1810H H H Et 2 —(CH₂)₅-(3-MeS-Ph) H H 1-1811 H H H Et 2 —(CH₂)₅-(4-MeS-Ph) HH 1-1812 H H H Et 2 —(CH₂)₅-(2,4-diMe-Ph) H H 1-1813 H H H Et 2—(CH₂)₅-(3,4-diMe-Ph) H H 1-1814 H H H Et 2 —(CH₂)₅-(3,5-diMe-Ph) H H1-1815 H H H Et 2 —(CH₂)₆-cPn H H 1-1816 H H H Et 2 —(CH₂)₆-cHx H H1-1817 H H H Et 2 —(CH₂)₆-cHx Me H 1-1818 H H H Et 2 —(CH₂)₆-cHx H Me1-1819 H H H Et 2 —(CH₂)₆-cHx F H 1-1820 H H H Et 2 —(CH₂)₆-cHx H F1-1821 H H Me Et 2 —(CH₂)₆-cHx H H 1-1822 Me H H Et 2 —(CH₂)₆-cHx H H1-1823 CO₂Me H H Et 2 —(CH₂)₆-cHx H H 1-1824 H H H Et 2—(CH₂)₆-(4-F-cHx) H H 1-1825 H H H Et 2 —(CH₂)₆-(4-Cl-cHx) H H 1-1826 HH H Et 2 —(CH₂)₆-(4-Br-cHx) H H 1-1827 H H H Et 2 —(CH₂)₆-(4-Me-cHx) H H1-1828 H H H Et 2 —(CH₂)₆-(4-Et-cHx) H H 1-1829 H H H Et 2—(CH₂)₆-(4-Pr-cHx) H H 1-1830 H H H Et 2 —(CH₂)₆-(4-iPr-cHx) H H 1-1831H H H Et 2 —(CH₂)₆-(4-Bu-cHx) H H 1-1832 H H H Et 2 —(CH₂)₆-(4-CF₃-cHx)H H 1-1833 H H H Et 2 —(CH₂)₆-(4-MeO-cHx) H H 1-1834 H H H Et 2—(CH₂)₆-(4-EtO-cHx) H H 1-1835 H H H Et 2 —(CH₂)₆-(4-PrO-cHx) H H 1-1836H H H Et 2 —(CH₂)₆-(4-iPrO-cHx) H H 1-1837 H H H Et 2—(CH₂)₆-(3-MeS-cHx) H H 1-1838 H H H Et 2 —(CH₂)₆-(4-MeS-cHx) H H 1-1839H H H Et 2 —(CH₂)₆-(2,4-diMe-cHx) H H 1-1840 H H H Et 2—(CH₂)₆-(3,4-diMe-cHx) H H 1-1841 H H H Et 2 —(CH₂)₆-(3,5-diMe-cHx) H H1-1842 H H H Et 2 —(CH₂)₆-Ph H H 1-1843 H H H Et 2 —(CH₂)₆-Ph Me H1-1844 H H H Et 2 —(CH₂)₆-Ph H Me 1-1845 H H H Et 2 —(CH₂)₆-Ph F H1-1846 H H H Et 2 —(CH₂)₆-Ph H F 1-1847 H H Me Et 2 —(CH₂)₆-Ph H H1-1848 Me H H Et 2 —(CH₂)₆-Ph H H 1-1849 CO₂Me H H Et 2 —(CH₂)₆-Ph H H1-1850 H H H Et 2 —(CH₂)₆-(4-F-Ph) H H 1-1851 H H H Et 2—(CH₂)₆-(4-Cl-Ph) H H 1-1852 H H H Et 2 —(CH₂)₆-(4-Br-Ph) H H 1-1853 H HH Et 2 —(CH₂)₆-(4-Me-Ph) H H 1-1854 H H H Et 2 —(CH₂)₆-(4-Et-Ph) H H1-1855 H H H Et 2 —(CH₂)₆-(4-Pr-Ph) H H 1-1856 H H H Et 2—(CH₂)₆-(4-iPr-Ph) H H 1-1857 H H H Et 2 —(CH₂)₆-(4-Bu-Ph) H H 1-1858 HH H Et 2 —(CH₂)₆-(4-CF₃-Ph) H H 1-1859 H H H Et 2 —(CH₂)₆-(4-MeO-Ph) H H1-1860 H H H Et 2 —(CH₂)₆-(4-EtO-Ph) H H 1-1861 H H H Et 2—(CH₂)₆-(4-PrO-Ph) H H 1-1862 H H H Et 2 —(CH₂)₆-(4-iPrO-Ph) H H 1-1863H H H Et 2 —(CH₂)₆-(3-MeS-Ph) H H 1-1864 H H H Et 2 —(CH₂)₆-(4-MeS-Ph) HH 1-1865 H H H Et 2 —(CH₂)₆-(2,4-diMe-Ph) H H 1-1866 H H H Et 2—(CH₂)₆-(3,4-diMe-Ph) H H 1-1867 H H H Et 2 —(CH₂)₆-(3,5-diMe-Ph) H H1-1868 H H H Et 2 —(CH₂)₇-cHx H H 1-1869 H H H Et 2 —(CH₂)₇-Ph H H1-1870 H H H Et 2 —CH═CH-cHx H H 1-1871 H H H Et 2 —CH═CH-Ph H H 1-1872H H H Et 2 —CH═CH—(CH₂)₃-cHx H H 1-1873 H H Me Et 2 —CH═CH—(CH₂)₃-cHx HH 1-1874 Me H H Et 2 —CH═CH—(CH₂)₃-cHx H H 1-1875 CO₂Me H H Et 2—CH═CH—(CH₂)₃-cHx H H 1-1876 H H H Et 2 —CH═CH—(CH₂)₃-Ph H H 1-1877 H HMe Et 2 —CH═CH—(CH₂)₃-Ph H H 1-1878 Me H H Et 2 —CH═CH—(CH₂)₃-Ph H H1-1879 CO₂Me H H Et 2 —CH═CH—(CH₂)₃-Ph H H 1-1880 H H H Et 2—CH═CH—(CH₂)₄-cHx H H 1-1881 H H Me Et 2 —CH═CH—(CH₂)₄-cHx H H 1-1882 MeH H Et 2 —CH═CH—(CH₂)₄-cHx H H 1-1883 CO₂Me H H Et 2 —CH═CH—(CH₂)₄-cHx HH 1-1884 H H H Et 2 —CH═CH—(CH₂)₄-Ph H H 1-1885 H H Me Et 2—CH═CH—(CH₂)₄-Ph H H 1-1886 Me H H Et 2 —CH═CH—(CH₂)₄-Ph H H 1-1887CO₂Me H H Et 2 —CH═CH—(CH₂)₄-Ph H H 1-1888 H H H Et 2 —CH═CH—CH₂O-cHx HH 1-1889 H H H Et 2 —CH═CH—CH₂O-Ph H H 1-1890 H H H Et 2—CH═CH—(CH₂)₂O-cHx H H 1-1891 H H H Et 2 —CH═CH—(CH₂)₂O-Ph H H 1-1892 HH H Et 2 —C≡C—CH₂-cHx H H 1-1893 H H Me Et 2 —C≡C—CH₂-cHx H H 1-1894 MeH H Et 2 —C≡C—CH₂-cHx H H 1-1895 CO₂Me H H Et 2 —C≡C—CH₂-cHx H H 1-1896H H H Et 2 —C≡C—CH₂-Ph H H 1-1897 H H Me Et 2 —C≡C—CH₂-Ph H H 1-1898 MeH H Et 2 —C≡C—CH₂-Ph H H 1-1899 CO₂Me H H Et 2 —C≡C—CH₂-Ph H H 1-1900 HH H Et 2 —C≡C—(CH₂)₂-cHx H H 1-1901 H H Me Et 2 —C≡C—(CH₂)₂-cHx H H1-1902 Me H H Et 2 —C≡C—(CH₂)₂-cHx H H 1-1903 CO₂Me H H Et 2—C≡C—(CH₂)₂-cHx H H 1-1904 H H H Et 2 —C≡C—(CH₂)₂-Ph H H 1-1905 H H MeEt 2 —C≡C—(CH₂)₂-Ph H H 1-1906 Me H H Et 2 —C≡C—(CH₂)₂-Ph H H 1-1907CO₂Me H H Et 2 —C≡C—(CH₂)₂-Ph H H 1-1908 H H H Et 2 —C≡C—(CH₂)₃-cPn H H1-1909 H H H Et 2 —C≡C—(CH₂)₃-cHx H H 1-1910 H H H Et 2 —C≡C—(CH₂)₃-cHxMe H 1-1911 H H H Et 2 —C≡C—(CH₂)₃-cHx H Me 1-1912 H H H Et 2—C≡C—(CH₂)₃-cHx F H 1-1913 H H H Et 2 —C≡C—(CH₂)₃-cHx H F 1-1914 H H MeEt 2 —C≡C—(CH₂)₃-cHx H H 1-1915 Me H H Et 2 —C≡C—(CH₂)₃-cHx H H 1-1916CO₂Me H H Et 2 —C≡C—(CH₂)₃-cHx H H 1-1917 H H H Et 2—C≡C—(CH₂)₃-(4-F-cHx) H H 1-1918 H H H Et 2 —C≡C—(CH₂)₃-(4-Cl-cHx) H H1-1919 H H H Et 2 —C≡C—(CH₂)₃-(4-Br-cHx) H H 1-1920 H H H Et 2—C≡C—(CH₂)₃-(4-Me-cHx) H H 1-1921 H H H Et 2 —C≡C—(CH₂)₃-(4-Et-cHx) H H1-1922 H H H Et 2 —C≡C—(CH₂)₃-(4-Pr-cHx) H H 1-1923 H H H Et 2—C≡C—(CH₂)₃-(4-iPr-cHx) H H 1-1924 H H H Et 2 —C≡C—(CH₂)₃-(4-Bu-cHx) H H1-1925 H H H Et 2 —C≡C—(CH₂)₃-(4-CF₃-cHx) H H 1-1926 H H H Et 2—C≡C—(CH₂)₃-(4-MeO-cHx) H H 1-1927 H H H Et 2 —C≡C—(CH₂)₃-(4-EtO-cHx) HH 1-1928 H H H Et 2 —C≡C—(CH₂)₃-(4-PrO-cHx) H H 1-1929 H H H Et 2—C≡C—(CH₂)₃-(4-iPrO-cHx) H H 1-1930 H H H Et 2 —C≡C—(CH₂)₃-(3-MeS-cHx) HH 1-1931 H H H Et 2 —C≡C—(CH₂)₃-(4-MeS-cHx) H H 1-1932 H H H Et 2—C≡C—(CH₂)₃-(2,4-diMe-cHx) H H 1-1933 H H H Et 2—C≡C—(CH₂)₃-(3,4-diMe-cHx) H H 1-1934 H H H Et 2—C≡C—(CH₂)₃-(3,5-diMe-cHx) H H 1-1935 H H H Et 2 —C≡C—(CH₂)₃-Ph H H1-1936 H H H Et 2 —C≡C—(CH₂)₃-Ph Me H 1-1937 H H H Et 2 —C≡C—(CH₂)₃-Ph HMe 1-1938 H H H Et 2 —C≡C—(CH₂)₃-Ph F H 1-1939 H H H Et 2 —C≡C—(CH₂)₃-PhH F 1-1940 H H Me Et 2 —C≡C—(CH₂)₃-Ph H H 1-1941 Me H H Et 2—C≡C—(CH₂)₃-Ph H H 1-1942 CO₂Me H H Et 2 —C≡C—(CH₂)₃-Ph H H 1-1943 H H HEt 2 —C≡C—(CH₂)₃-(4-F-Ph) H H 1-1944 H H H Et 2 —C≡C—(CH₂)₃-(4-Cl-Ph) HH 1-1945 H H H Et 2 —C≡C—(CH₂)₃-(4-Br-Ph) H H 1-1946 H H H Et 2—C≡C—(CH₂)₃-(4-Me-Ph) H H 1-1947 H H H Et 2 —C≡C—(CH₂)₃-(4-Et-Ph) H H1-1948 H H H Et 2 —C≡C—(CH₂)₃-(4-Pr-Ph) H H 1-1949 H H H Et 2—C≡C—(CH₂)₃-(4-iPr-Ph) H H 1-1950 H H H Et 2 —C≡C—(CH₂)₃-(4-Bu-Ph) H H1-1951 H H H Et 2 —C≡C—(CH₂)₃-(4-CF₃-Ph) H H 1-1952 H H H Et 2—C≡C—(CH₂)₃-(4-MeO-Ph) H H 1-1953 H H H Et 2 —C≡C—(CH₂)₃-(4-EtO-Ph) H H1-1954 H H H Et 2 —C≡C—(CH₂)₃-(4-PrO-Ph) H H 1-1955 H H H Et 2—C≡C—(CH₂)₃-(4-iPrO-Ph) H H 1-1956 H H H Et 2 —C≡C—(CH₂)₃-(3-MeS-Ph) H H1-1957 H H H Et 2 —C≡C—(CH₂)₃-(4-MeS-Ph) H H 1-1958 H H H Et 2—C≡C—(CH₂)₃-(2,4-diMe-Ph) H H 1-1959 H H H Et 2—C≡C—(CH₂)₃-(3,4-diMe-Ph) H H 1-1960 H H H Et 2—C≡C—(CH₂)₃-(3,5-diMe-Ph) H H 1-1961 H H H Et 2 —C≡C—(CH₂)₄-cPn H H1-1962 H H H Et 2 —C≡C—(CH₂)₄-cHx H H 1-1963 H H H Et 2 —C≡C—(CH₂)₄-cHxMe H 1-1964 H H H Et 2 —C≡C—(CH₂)₄-cHx H Me 1-1965 H H H Et 2—C≡C—(CH₂)₄-cHx F H 1-1966 H H H Et 2 —C≡C—(CH₂)₄-cHx H F 1-1967 H H MeEt 2 —C≡C—(CH₂)₄-cHx H H 1-1968 Me H H Et 2 —C≡C—(CH₂)₄-cHx H H 1-1969CO₂Me H H Et 2 —C≡C—(CH₂)₄-cHx H H 1-1970 H H H Et 2—C≡C—(CH₂)₄-(4-F-cHx) H H 1-1971 H H H Et 2 —C≡C—(CH₂)₄-(4-Cl-cHx) H H1-1972 H H H Et 2 —C≡C—(CH₂)₄-(4-Br-cHx) H H 1-1973 H H H Et 2—C≡C—(CH₂)₄-(4-Me-cHx) H H 1-1974 H H H Et 2 —C≡C—(CH₂)₄-(4-Et-cHx) H H1-1975 H H H Et 2 —C≡C—(CH₂)₄-(4-Pr-cHx) H H 1-1976 H H H Et 2—C≡C—(CH₂)₄-(4-iPr-cHx) H H 1-1977 H H H Et 2 —C≡C—(CH₂)₄-(4-Bu-cHx) H H1-1978 H H H Et 2 —C≡C—(CH₂)₄-(4-CF₃-cHx) H H 1-1979 H H H Et 2—C≡C—(CH₂)₄-(4-MeO-cHx) H H 1-1980 H H H Et 2 —C≡C—(CH₂)₄-(4-EtO-cHx) HH 1-1981 H H H Et 2 —C≡C—(CH₂)₄-(4-PrO-cHx) H H 1-1982 H H H Et 2—C≡C—(CH₂)₄-(4-iPrO-cHx) H H 1-1983 H H H Et 2 —C≡C—(CH₂)₄-(4-MeS-cHx) HH 1-1984 H H H Et 2 —C≡C—(CH₂)₄-(2,4-diMe-cHx) H H 1-1985 H H H Et 2—C≡C—(CH₂)₄-(3,4-diMe-cHx) H H 1-1986 H H H Et 2—C≡C—(CH₂)₄-(3,5-diMe-cHx) H H 1-1987 H H H Et 2 —C≡C—(CH₂)₄-Ph H H1-1988 H H H Et 2 —C≡C—(CH₂)₄-Ph Me H 1-1989 H H H Et 2 —C≡C—(CH₂)₄-Ph HMe 1-1990 H H H Et 2 —C≡C—(CH₂)₄-Ph F H 1-1991 H H H Et 2 —C≡C—(CH₂)₄-PhH F 1-1992 H H Me Et 2 —C≡C—(CH₂)₄-Ph H H 1-1993 Me H H Et 2—C≡C—(CH₂)₄-Ph H H 1-1994 CO₂Me H H Et 2 —C≡C—(CH₂)₄-Ph H H 1-1995 H H HEt 2 —C≡C—(CH₂)₄-(4-F-Ph) H H 1-1996 H H H Et 2 —C≡C—(CH₂)₄-(4-Cl-Ph) HH 1-1997 H H H Et 2 —C≡C—(CH₂)₄-(4-Br-Ph) H H 1-1998 H H H Et 2—C≡C—(CH₂)₄-(4-Me-Ph) H H 1-1999 H H H Et 2 —C≡C—(CH₂)₄-(4-Et-Ph) H H1-2000 H H H Et 2 —C≡C—(CH₂)₄-(4-Pr-Ph) H H 1-2001 H H H Et 2—C≡C—(CH₂)₄-(4-iPr-Ph) H H 1-2002 H H H Et 2 —C≡C—(CH₂)₄-(4-Bu-Ph) H H1-2003 H H H Et 2 —C≡C—(CH₂)₄-(4-CF₃-Ph) H H 1-2004 H H H Et 2—C≡C—(CH₂)₄-(4-MeO-Ph) H H 1-2005 H H H Et 2 —C≡C—(CH₂)₄-(4-EtO-Ph) H H1-2006 H H H Et 2 —C≡C—(CH₂)₄-(4-PrO-Ph) H H 1-2007 H H H Et 2—C≡C—(CH₂)₄-(4-iPrO-Ph) H H 1-2008 H H H Et 2 —C≡C—(CH₂)₄-(3-MeS-Ph) H H1-2009 H H H Et 2 —C≡C—(CH₂)₄-(4-MeS-Ph) H H 1-2010 H H H Et 2—C≡C—(CH₂)₄-(2,4-diMe-Ph) H H 1-2011 H H H Et 2—C≡C—(CH₂)₄-(3,4-diMe-Ph) H H 1-2012 H H H Et 2—C≡C—(CH₂)₄-(3,5-diMe-Ph) H H 1-2013 H H H Et 2 —C≡C—(CH₂)₅-cHx H H1-2014 H H Me Et 2 —C≡C—(CH₂)₅-cHx H H 1-2015 Me H H Et 2—C≡C—(CH₂)₅-cHx H H 1-2016 CO₂Me H H Et 2 —C≡C—(CH₂)₅-cHx H H 1-2017 H HH Et 2 —C≡C—(CH₂)₅-Ph H H 1-2018 H H Me Et 2 —C≡C—(CH₂)₅-Ph H H 1-2019Me H H Et 2 —C≡C—(CH₂)₅-Ph H H 1-2020 CO₂Me H H Et 2 —C≡C—(CH₂)₅-Ph H H1-2021 H H H Et 2 —C≡C—(CH₂)₆-cHx H H 1-2022 H H Me Et 2 —C≡C—(CH₂)₆-cHxH H 1-2023 Me H H Et 2 —C≡C—(CH₂)₆-cHx H H 1-2024 CO₂Me H H Et 2—C≡C—(CH₂)₆-cHx H H 1-2025 H H H Et 2 —C≡C—(CH₂)₆-Ph H H 1-2026 H H MeEt 2 —C≡C—(CH₂)₆-Ph H H 1-2027 Me H H Et 2 —C≡C—(CH₂)₆-Ph H H 1-2028CO₂Me H H Et 2 —C≡C—(CH₂)₆-Ph H H 1-2029 H H H Et 2 —C≡C—CH₂O-cHx H H1-2030 H H Me Et 2 —C≡C—CH₂O-cHx H H 1-2031 Me H H Et 2 —C≡C.CH₂O-cHx HH 1-2032 CO₂Me H H Et 2 —C≡C—CH₂O-cHx H H 1-2033 H H H Et 2 —C≡C—CH₂O-PhH H 1-2034 H H Me Et 2 —C≡C—CH₂O-Ph H H 1-2035 Me H H Et 2 —C≡C—CH₂O-PhH H 1-2036 CO₂Me H H Et 2 —C≡C—CH₂O-Ph H H 1-2037 H H H Et 2—C≡C—(CH₂)₂O-cPn H H 1-2038 H H H Et 2 —C≡C—(CH₂)₂O-cHx H H 1-2039 H H HEt 2 —C≡C—(CH₂)₂O-cHx Me H 1-2040 H H H Et 2 —C≡C—(CH₂)₂O-cHx H Me1-2041 H H H Et 2 —C≡C—(CH₂)₂O-cHx F H 1-2042 H H H Et 2—C≡C—(CH₂)₂O-cHx H F 1-2043 H H Me Et 2 —C≡C—(CH₂)₂O-cHx H H 1-2044 Me HH Et 2 —C≡C—(CH₂)₂O-cHx H H 1-2045 CO₂Me H H Et 2 —C≡C—(CH₂)₂O-cHx H H1-2046 H H H Et 2 —C≡C—(CH₂)₂O-(4-F-cHx) H H 1-2047 H H H Et 2—C≡C—(CH₂)₂O-(4-Cl-cHx) H H 1-2048 H H H Et 2 —C≡C—(CH₂)₂O-(4-Br-cHx) HH 1-2049 H H H Et 2 —C≡C—(CH₂)₂O-(4-Me-cHx) H H 1-2050 H H H Et 2—C≡C—(CH₂)₂O-(4-Et-cHx) H H 1-2051 H H H Et 2 —C≡C—(CH₂)₂O-(4-Pr-cHx) HH 1-2052 H H H Et 2 —C≡C—(CH₂)₂O-(4-iPr-cHx) H H 1-2053 H H H Et 2—C≡C—(CH₂)₂O-(4-Bu-cHx) H H 1-2054 H H H Et 2 —C≡C—(CH₂)₂O-(4-CF₃-cHx) HH 1-2055 H H H Et 2 —C≡C—(CH₂)₂O-(4-MeO-cHx) H H 1-2056 H H H Et 2—C≡C—(CH₂)₂O-(4-EtO-cHx) H H 1-2057 H H H Et 2 —C≡C—(CH₂)₂O-(4-PrO-cHx)H H 1-2058 H H H Et 2 —C≡C—(CH₂)₂O-(4-iPrO-cHx) H H 1-2059 H H H Et 2—C≡C—(CH₂)₂O-(3-MeS-cHx) H H 1-2060 H H H Et 2 —C≡C—(CH₂)₂O-(4-MeS-cHx)H H 1-2061 H H H Et 2 —C≡C—(CH₂)₂O-(2,4-diMe-cHx) H H 1-2062 H H H Et 2—C≡C—(CH₂)₂O-(3,4-diMe-cHx) H H 1-2063 H H H Et 2—C≡C—(CH₂)₂O-(3,5-diMe-cHx) H H 1-2064 H H H Et 2 —C≡C—(CH₂)₂O-Ph H H1-2065 H H H Et 2 —C≡C—(CH₂)₂O-Ph Me H 1-2066 H H H Et 2 —C≡C—(CH₂)₂O-PhH Me 1-2067 H H H Et 2 —C≡C—(CH₂)₂O-Ph F H 1-2068 H H H Et 2—C≡C—(CH₂)₂O-Ph H F 1-2069 H H Me Et 2 —C≡C—(CH₂)₂—OCH₂-Ph H H 1-2070 MeH H Et 2 —C≡C—(CH₂)₂O-Ph H H 1-2071 CO₂Me H H Et 2 —C≡C—(CH₂)₂O-Ph H H1-2072 H H H Et 2 —C≡C—(CH₂)₂O-(4-F-Ph) H H 1-2073 H H H Et 2—C≡C—(CH₂)₂O-(4-Cl-Ph) H H 1-2074 H H H Et 2 —C≡C—(CH₂)₂O-(4-Br-Ph) H H1-2075 H H H Et 2 —C≡C—(CH₂)₂O-(4-Me-Ph) H H 1-2076 H H H Et 2—C≡C—(CH₂)₂O-(4-Et-Ph) H H 1-2077 H H H Et 2 —C≡C—(CH₂)₂O-(4-Pr-Ph) H H1-2078 H H H Et 2 —C≡C—(CH₂)₂O-(4-iPr-Ph) H H 1-2079 H H H Et 2—C≡C—(CH₂)₂O-(4-Bu-Ph) H H 1-2080 H H H Et 2 —C≡C—(CH₂)₂O-(4-CF₃-Ph) H H1-2081 H H H Et 2 —C≡C—(CH₂)₂O-(4-MeO-Ph) H H 1-2082 H H H Et 2—C≡C—(CH₂)₂O-(4-EtO-Ph) H H 1-2083 H H H Et 2 —C≡C—(CH₂)₂O-(4-PrO-Ph) HH 1-2084 H H H Et 2 —C≡C—(CH₂)₂O-(4-iPrO-Ph) H H 1-2085 H H H Et 2—C≡C—(CH₂)₂O-(4-MeS-Ph) H H 1-2086 H H H Et 2 —C≡C—(CH₂)₂O-(2,4-diMe-Ph)H H 1-2087 H H H Et 2 —C≡C—(CH₂)₂O-(3,4-diMe-Ph) H H 1-2088 H H H Et 2—C≡C—(CH₂)₂O-(3,5-diMe-Ph) H H 1-2089 H H H Et 2 —CO—(CH₂)₃-cHx H H1-2090 H H Me Et 2 —CO—(CH₂)₃-cHx H H 1-2091 Me H H Et 2 —CO—(CH₂)₃-cHxH H 1-2092 CO₂Me H H Et 2 —CO—(CH₂)₃-cHx H H 1-2093 H H H Et 2—CO—(CH₂)₃-Ph H H 1-2094 H H Me Et 2 —CO—(CH₂)₃-Ph H H 1-2095 Me H H Et2 —CO—(CH₂)₃-Ph H H 1-2096 CO₂Me H H Et 2 —CO—(CH₂)₃-Ph H H 1-2097 H H HEt 2 —CO—(CH₂)₄-cHx H H 1-2098 H H Me Et 2 —CO—(CH₂)₄-cHx H H 1-2099 MeH H Et 2 —CO—(CH₂)₄-cHx H H 1-2100 CO₂Me H H Et 2 —CO—(CH₂)₄-cHx H H1-2101 H H H Et 2 —CO—(CH₂)₄-Ph H H 1-2102 H H Me Et 2 —CO—(CH₂)₄-Ph H H1-2103 Me H H Et 2 —CO—(CH₂)₄-Ph H H 1-2104 CO₂Me H H Et 2 —CO—(CH₂)₄-PhH H 1-2105 H H H Et 2 —CO—(CH₂)₅-cHx H H 1-2106 H H Me Et 2—CO—(CH₂)₅-cHx H H 1-2107 Me H H Et 2 —CO—(CH₂)₅-cHx H H 1-2108 CO₂Me HH Et 2 —CO—(CH₂)₅-cHx H H 1-2109 H H H Et 2 —CO—(CH₂)₅-Ph H H 1-2110 H HMe Et 2 —CO—(CH₂)₅-Ph H H 1-2111 Me H H Et 2 —CO—(CH₂)₅-Ph H H 1-2112CO₂Me H H Et 2 —CO—(CH₂)₅-Ph H H 1-2113 H H H Et 2 —CH(OH)—(CH₂)₄-cHx HH 1-2114 H H Me Et 2 —CH(OH)—(CH₂)₄-cHx H H 1-2115 Me H H Et 2—CH(OH)—(CH₂)₄-cHX H H 1-2116 CO₂Me H H Et 2 —CH(OH)—(CH₂)₄—cHx H H1-2117 H H H Et 2 —CH(OH)—(CH₂)₄-Ph H H 1-2118 H H Me Et 2—CH(OH)—(CH₂)₄-Ph H H 1-2119 Me H H Et 2 —CH(OH)—(CH₂)₄-Ph H H 1-2120CO₂Me H H Et 2 —CH(OH)—(CH₂)₄-Ph H H 1-2121 H H H Et 2—CH(OH)—(CH₂)₅-cHx H H 1-2122 H H Me Et 2 —CH(OH)—(CH₂)₅-cHX H H 1-2123Me H H Et 2 —CH(OH)—(CH₂)₅-cHx H H 1-2124 CO₂Me H H Et 2—CH(OH)—(CH₂)₅-cHX H H 1-2125 H H H Et 2 —CH(OH)—(CH₂)₅-Ph H H 1-2126 HH Me Et 2 —CH(OH)—(CH₂)₅-Ph H H 1-2127 Me H H Et 2 —CH(OH)—(CH₂)₅-Ph H H1-2128 CO₂Me H H Et 2 —CH(OH)—(CH₂)₅-Ph H H 1-2129 H H H Et 2-4-(cHx-CH₂O)Ph H H 1-2130 H H Me Et 2 -4-(cHx-CH₂O)Ph H H 1-2131 Me H HEt 2 -4-(cHx-CH₂O)Ph H H 1-2132 CO₂Me H H Et 2 -4-(cHx-CH₂O)Ph H H1-2133 H H H Et 2 -4-[cHx-(CH₂)₂O]Ph H H 1-2134 H H H Et 2-4-[cHx-(CH₂)₃O]Ph H H 1-2135 H H H Et 2 -(4-BzO-Ph) H H 1-2136 H H MeEt 2 -(4-BzO-Ph) H H 1-2137 Me H H Et 2 -(4-BzO-Ph) H H 1-2138 CO₂Me H HEt 2 -(4-BzO-Ph) H H 1-2139 H H H Et 2 -(4-BzO-2-F-Ph) H H 1-2140 H H HEt 2 -(4-BzO-3-F-Ph) H H 1-2141 H H H Et 2 -(4-BzO-2,3-diF-Ph) H H1-2142 H H H Et 2 -(4-BzO-2-Cl-Ph) H H 1-2143 H H H Et 2-(4-BzO-3-Cl-Ph) H H 1-2144 H H H Et 2 -(4-BzO-2,3-diCl-Ph) H H 1-2145 HH H Et 2 -(4-BzO-2-Me-Ph) H H 1-2146 H H H Et 2 -(4-BzO-3-Me-Ph) H H1-2147 H H H Et 2 -(4-BzO-2,3-diMe-Ph) H H 1-2148 H H H Et 2-4-[Ph-(CH₂)₂O]-Ph H H 1-2149 H H H Et 2 -4-[Ph-(CH₂)₃O]-Ph H H 1-2150 HH H Pr 2 —(CH₂)₅-cHx H H 1-2151 H H H Pr 2 —(CH₂)₅-Ph H H 1-2152 H H HPr 2 —(CH₂)₆-cHx H H 1-2153 H H H Pr 2 —(CH₂)₆-Ph H H 1-2154 H H H Pr 2—C≡C—CH₂-cHx H H 1-2155 H H H Pr 2 —C≡C—(CH₂)₃-cHx H H 1-2156 H H H Pr 2—C≡C—(CH₂)₃-Ph H H 1-2157 H H H Pr 2 —C≡C—(CH₂)₄-cHx H H 1-2158 H H H Pr2 —C≡C—(CH₂)₄-Ph H H 1-2159 Me H H Pr 2 —C≡C—CH₂O-Ph H H 1-2160 CO₂Me HH Pr 2 —C≡C—CH₂O-Ph H H 1-2161 H H H Pr 2 —C≡C—(CH₂)₂O-cHx H H 1-2162 HH H Pr 2 —C≡C—(CH₂)₂O-Ph H H 1-2163 H H H Pr 2 -4-(cHx-CH₂O)Ph H H1-2164 H H H Pr 2 -(4-BzO-Ph) H H 1-2165 H H H Me 3 —(CH₂)₅-cHx H H1-2166 H H H Me 3 —(CH₂)₆-cHx H H 1-2167 H H H Me 3 —CH═CH—(CH₂)₃-cHx HH 1-2168 H H H Me 3 —CH═CH—(CH₂)₄-cHx H H 1-2169 H H H Me 3—C≡C—(CH₂)₃-cHx H H 1-2170 H H H Me 3 —C≡C—(CH₂)₄-cHx H H 1-2171 H H HMe 3 —CO—(CH₂)₄-cHx H H 1-2172 H H H Me 3 —CO—(CH₂)₅-cHx H H 1-2173 H HH Me 3 —CO—(CH₂)₄-Ph H H 1-2174 H H H Me 3 —CO—(CH₂)₅-Ph H H 1-2175 H HH Me 3 —CH(OH)—(CH₂)₄-cHx H H 1-2176 H H H Me 3 —CH(OH)—(CH₂)₅-cHx H H1-2177 H H H Me 3 -4-(cHx-CH₂O)Ph H H 1-2178 H H H Me 3 -(4-BzO-Ph) H H1-2179 H H H Me 3 —C≡C—CH₂O-cPn H H 1-2180 H H H Me 3 —C≡C—(CH₂)₂O-cPn HH 1-2181 H H H Me 3 —C≡C—CH₂O-cHx H H 1-2182 H H H Me 3 —C≡C—(CH₂)₂O-cHxH H 1-2183 H H H Me 3 —C≡C—CH₂O-Ph H H 1-2184 H H H Me 3 —C≡C—(CH₂)₂O-PhH H 1-2185 H H H Me 2 —(CH₂)₄-(3-F-Ph) H H 1-2186 H H H Me 2—(CH₂)₄-(3,4-diF-Ph) H H 1-2187 H H H Me 2 —(CH₂)₄-(3,5-diF-Ph) H H1-2188 H H H Me 2 —(CH₂)₄-(3-Cl-Ph) H H 1-2189 H H H Me 2—(CH₂)₄-(4-Cl-Ph) H H 1-2190 H H H Me 2 —(CH₂)₄-(3,4-diCl-Ph) H H 1-2191H H H Me 2 —(CH₂)₄-(3,5-diCl-Ph) H H 1-2192 H H H Me 2 —(CH₂)₄-(3-Me-Ph)H H 1-2193 H H H Me 2 —(CH₂)₄-(3,4-diMe-Ph) H H 1-2194 H H H Me 2—(CH₂)₄-(3,5-diMe-Ph) H H 1-2195 H H H Me 2 —(CH₂)₄-(3-CF₃-Ph) H H1-2196 H H H Me 2 —(CH₂)₄-(3,4-diCF₃-Ph) H H 1-2197 H H H Me 2—(CH₂)₄-(3,5-diCF₃-Ph) H H 1-2198 H H H Me 2 —(CH₂)₄-(3-MeO-Ph) H H1-2199 H H H Me 2 —(CH₂)₄-(3,4-diMeO-Ph) H H 1-2200 H H H Me 2—(CH₂)₄-(3,5-diMeO-Ph) H H 1-2201 H H H Me 2 —(CH₂)₄-(3,4,5-triMeO-Ph) HH 1-2202 H H H Me 2 —(CH₂)₄-(3-Ac-Ph) H H 1-2203 H H H Me 2—(CH₂)₄-(4-Ac-Ph) H H 1-2204 H H H Me 2 —(CH₂)₅-(3,4-diF-Ph) H H 1-2205H H H Me 2 —(CH₂)₅-(3,5-diF-Ph) H H 1-2206 H H H Me 2 —(CH₂)₅-(3-Cl-Ph)H H 1-2207 H H H Me 2 —(CH₂)₅-(3,4-diCl-Ph) H H 1-2208 H H H Me 2—(CH₂)₅-(3,5-diCl-Ph) H H 1-2209 H H H Me 2 —(CH₂)₅-(3,4-diCF₃-Ph) H H1-2210 H H H Me 2 —(CH₂)₅-(3,5-diCF₃-Ph) H H 1-2211 H H H Me 2—(CH₂)₅-(3,4-diMeO-Ph) H H 1-2212 H H H Me 2 —(CH₂)₅-(3,5-diMeO-Ph) H H1-2213 H H H Me 2 —(CH₂)₅-(3,4,5-triMeO-Ph) H H 1-2214 H H H Me 2—(CH₂)₅-(3-Ac-Ph) H H 1-2215 H H H Me 2 —(CH₂)₅-(4-Ac-Ph) H H 1-2216 H HH Me 2 —(CH₂)₃—O-(3-F-Ph) H H 1-2217 H H H Me 2 —(CH₂)₃—O-(3,4-diF-Ph) HH 1-2218 H H H Me 2 —(CH₂)₃—O-(3,5-diF-Ph) H H 1-2219 H H H Me 2—(CH₂)₃—O-(3-Me-Ph) H H 1-2220 H H H Me 2 —(CH₂)₃—O-(3,4-diMe-Ph) H H1-2221 H H H Me 2 —(CH₂)₃—O-(3,5-diMe-Ph) H H 1-2222 H H H Me 2—(CH₂)₃—O-(3-CF₃-Ph) H H 1-2223 H H H Me 2 —(CH₂)₃—O-(3,4-diCF₃-Ph) H H1-2224 H H H Me 2 —(CH₂)₃—O-(3,5-diCF₃-Ph) H H 1-2225 H H H Me 2—(CH₂)₃—O-(3-MeO-Ph) H H 1-2226 H H H Me 2 —(CH₂)₃—O-(3,4-diMeO-Ph) H H1-2227 H H H Me 2 —(CH₂)₃—O-(3,5-diMeO-Ph) H H 1-2228 H H H Me 2—(CH₂)₃—O-(3,4,5-triMeO-Ph) H H 1-2229 H H H Me 2 —(CH₂)₃—O-(3-Ac-Ph) HH 1-2230 H H H Me 2 —(CH₂)₃—O-(4-Ac-Ph) H H 1-2231 H H H Me 2—(CH₂)₄—O-(3,4-diF-Ph) H H 1-2232 H H H Me 2 —(CH₂)₄—O-(3,5-diF-Ph) H H1-2233 H H H Me 2 —(CH₂)₄—O-(3,4-diMeO-Ph) H H 1-2234 H H H Me 2—(CH₂)₄—O-(3,5-diMeO-Ph) H H 1-2235 H H H Me 2—(CH₂)₄—O-(3,4,5-triMeO-Ph) H H 1-2236 H H H Me 2 —(CH₂)₄—O-(3-Ac-Ph) HH 1-2237 H H H Me 2 —(CH₂)₄—O-(4-Ac-Ph) H H 1-2238 H H H Me 2—C≡C—(CH₂)₂-(3-F-Ph) H H 1-2239 H H H Me 2 —C≡C—(CH₂)₂-(3,4-diF-Ph) H H1-2240 H H H Me 2 —C≡C—(CH₂)₂-(3,5-diF-Ph) H H 1-2241 H H H Me 2—C≡C—(CH₂)₂-(3-Cl-Ph) H H 1-2242 H H H Me 2 —C≡C—(CH₂)₂-(4-Cl-Ph) H H1-2243 H H H Me 2 —C≡C—(CH₂)₂-(3,4-diCl-Ph) H H 1-2244 H H H Me 2—C≡C—(CH₂)₂-(3,5-diCl-Ph) H H 1-2245 H H H Me 2 —C≡C—(CH₂)₂-(3-Me-Ph) HH 1-2246 H H H Me 2 —C≡C—(CH₂)₂-(3,4-diMe-Ph) H H 1-2247 H H H Me 2—C≡C—(CH₂)₂-(3,5-diMe-Ph) H H 1-2248 H H H Me 2 —C≡C—(CH₂)₂-(3-CF₃-Ph) HH 1-2249 H H H Me 2 —C≡C—(CH₂)₂-(3,4-diCF₃-Ph) H H 1-2250 H H H Me 2—C≡C—(CH₂)₂-(3,5-diCF₃-Ph) H H 1-2251 H H H Me 2 —C≡C—(CH₂)₂-(3-MeO-Ph)H H 1-2252 H H H Me 2 —C≡C—(CH₂)₂-(3,4-diMeO-Ph) H H 1-2253 H H H Me 2—C≡C—(CH₂)₂-(3,5-diMeO-Ph) H H 1-2254 H H H Me 2—C≡C—(CH₂)₂-(3,4,5-triMeO-Ph) H H 1-2255 H H H Me 2—C≡C—(CH₂)₂-(3-Ac-Ph) H H 1-2256 H H H Me 2 —C≡C—(CH₂)₂-(4-Ac-Ph) H H1-2257 H H H Me 2 —C≡C—(CH₂)₃-(3,4-diF-Ph) H H 1-2258 H H H Me 2—C≡C—(CH₂)₃-(3,5-diF-Ph) H H 1-2259 H H H Me 2 —C≡C—(CH₂)₃-(3-Cl-Ph) H H1-2260 H H H Me 2 —C≡C—(CH₂)₃-(3,4-diCl-Ph) H H 1-2261 H H H Me 2—C≡C—(CH₂)₃-(3,5-diCl-Ph) H H 1-2262 H H H Me 2—C≡C—(CH₂)₃-(3,4-diCF₃-Ph) H H 1-2263 H H H Me 2—C≡C—(CH₂)₃-(3,5-diCF₃-Ph) H H 1-2264 H H H Me 2—C≡C—(CH₂)₃-(3,4-diMeO-Ph) H H 1-2265 H H H Me 2—C≡C—(CH₂)₃-(3,5-diMeO-Ph) H H 1-2266 H H H Me 2—C≡C—(CH₂)₃-(3,4,5-triMeO-Ph) H H 1-2267 H H H Me 2—C≡C—(CH₂)₃-(3-Ac-Ph) H H 1-2268 H H H Me 2 —C≡C—(CH₂)₃-(4-Ac-Ph) H H1-2269 H H H Me 2 —C≡C—CH₂—O-(3-F-Ph) H H 1-2270 H H H Me 2—C≡C—CH₂—O-(3,4-diF-Ph) H H 1-2271 H H H Me 2 —C≡C—CH₂—O-(3,5-diF-Ph) HH 1-2272 H H H Me 2 —C≡C—CH₂—O-(3-Cl-Ph) H H 1-2273 H H H Me 2—C≡C—CH₂—O-(4-Cl-Ph) H H 1-2274 H H H Me 2 —C≡C—CH₂—O-(3,4-diCl-Ph) H H1-2275 H H H Me 2 —C≡C—CH₂—O-(3,5-diCl-Ph) H H 1-2276 H H H Me 2—C≡C—CH₂—O-(3-Me-Ph) H H 1-2277 H H H Me 2 —C≡C—CH₂—O-(2,4-diMe-Ph) H H1-2278 H H H Me 2 —C≡C—CH₂—O-(3,4-diMe-Ph) H H 1-2279 H H H Me 2—C≡C—CH₂—O-(3,5-diMe-Ph) H H 1-2280 H H H Me 2 —C≡C—CH₂—O-(3-CF₃-Ph) H H1-2281 H H H Me 2 —C≡C—CH₂—O-(3,4-diCF₃-Ph) H H 1-2282 H H H Me 2—C≡C—CH₂—O-(3,5-diCF₃-Ph) H H 1-2283 H H H Me 2 —C≡C—CH₂—O-(3-MeO-Ph) HH 1-2284 H H H Me 2 —C≡C—CH₂—O-(3,4-diMeO-Ph) H H 1-2285 H H H Me 2—C≡C—CH₂—O-(3,5-diMeO-Ph) H H 1-2286 H H H Me 2—C≡C—CH₂—O-(3,4,5-triMeO-Ph) H H 1-2287 H H H Me 2 —C≡C—CH₂—O-(3-Ac-Ph)H H 1-2288 H H H Me 2 —C≡C—CH₂—O-(4-Ac-Ph) H H 1-2289 H H H Me 2—C≡C—CH₂—O-(4-CO2H-Ph) H H 1-2290 H H H Me 2 —C≡C—(CH₂)₂—O-(3,4-diF-Ph)H H 1-2291 H H H Me 2 —C≡C—(CH₂)₂—O-(3,5-diF-Ph) H H 1-2292 H H H Me 2—C≡C—(CH₂)₂—O-(3-Cl-Ph) H H 1-2293 H H H Me 2—C≡C—(CH₂)₂—O-(3,4-diCl-Ph) H H 1-2294 H H H Me 2—C≡C—(CH₂)₂—O-(3,5-diCl-Ph) H H 1-2295 H H H Me 2—C≡C—(CH₂)₂—O-(3,4-diCF₃-Ph) H H 1-2296 H H H Me 2—C≡C—(CH₂)₂—O-(3,5-diCF₃-Ph) H H 1-2297 H H H Me 2—C≡C—(CH₂)₂—O-(3,4-diMeO-Ph) H H 1-2298 H H H Me 2—C≡C—(CH₂)₂—O-(3,5-diMeO-Ph) H H 1-2299 H H H Me 2—C≡C—(CH₂)₂—O-(3,4,5-triMeO-Ph) H H 1-2300 H H H Me 2—C≡C—(CH₂)₂—O-(3-Ac-Ph) H H 1-2301 H H H Me 2 —C≡C—(CH₂)₂—O-(4-Ac-Ph) HH 1-2302 H H H Me 2 —CO—(CH₂)₃-(3-F-Ph) H H 1-2303 H H H Me 2—CO—(CH₂)₃-(4-F-Ph) H H 1-2304 H H H Me 2 —CO—(CH₂)₃-(3,4-diF-Ph) H H1-2305 H H H Me 2 —CO—(CH₂)₃-(3,5-diF-Ph) H H 1-2306 H H H Me 2—CO—(CH₂)₃-(3-Cl-Ph) H H 1-2307 H H H Me 2 —CO—(CH₂)₃-(4-Cl-Ph) H H1-2308 H H H Me 2 —CO—(CH₂)₃-(3,4-diCl-Ph) H H 1-2309 H H H Me 2—CO—(CH₂)₃-(3,5-diCl-Ph) H H 1-2310 H H H Me 2 —CO—(CH₂)₃-(3-Me-Ph) H H1-2311 H H H Me 2 —CO—(CH₂)₃-(4-Me-Ph) H H 1-2312 H H H Me 2—CO—(CH₂)₃-(3,4-diMe-Ph) H H 1-2313 H H H Me 2 —CO—(CH₂)₃-(3,5-diMe-Ph)H H 1-2314 H H H Me 2 —CO—(CH₂)₃-(3-Et-Ph) H H 1-2315 H H H Me 2—CO—(CH₂)₃-(4-Et-Ph) H H 1-2316 H H H Me 2 —CO—(CH₂)₃-(3-CF₃-Ph) H H1-2317 H H H Me 2 —CO—(CH₂)₃-(4-CF₃-Ph) H H 1-2318 H H H Me 2—CO—(CH₂)₃-(3,4-diCF₃-Ph) H H 1-2319 H H H Me 2—CO—(CH₂)₃-(3,5-diCF₃-Ph) H H 1-2320 H H H Me 2 —CO—(CH₂)₃-(3-MeO-Ph) HH 1-2321 H H H Me 2 —CO—(CH₂)₃-(4-MeO-Ph) H H 1-2322 H H H Me 2—CO—(CH₂)₃-(3,4-diMeO-Ph) H H 1-2323 H H H Me 2—CO—(CH₂)₃-(3,5-diMeO-Ph) H H 1-2324 H H H Me 2—CO—(CH₂)₃-(3,4,5-triMeO-Ph) H H 1-2325 H H H Me 2 —CO—(CH₂)₃-(4-MeS-Ph)H H 1-2326 H H H Me 2 —CO—(CH₂)₃-(3-Ac-Ph) H H 1-2327 H H H Me 2—CO—(CH₂)₃-(4-Ac-Ph) H H 1-2328 H H H Me 2 —CO—(CH₂)₄-(3-F-Ph) H H1-2329 H H H Me 2 —CO—(CH₂)₄-(3,4-diF-Ph) H H 1-2330 H H H Me 2—CO—(CH₂)₄-(3,5-diF-Ph) H H 1-2331 H H H Me 2 —CO—(CH₂)₄-(3-Cl-Ph) H H1-2332 H H H Me 2 —CO—(CH₂)₄-(4-Cl-Ph) H H 1-2333 H H H Me 2—CO—(CH₂)₄-(3,4-diCl-Ph) H H 1-2334 H H H Me 2 —CO—(CH₂)₄-(3,5-diCl-Ph)H H 1-2335 H H H Me 2 —CO—(CH₂)₄-(3-Me-Ph) H H 1-2336 H H H Me 2—CO—(CH₂)₄-(3,4-diMe-Ph) H H 1-2337 H H H Me 2 —CO—(CH₂)₄-(3,5-diMe-Ph)H H 1-2338 H H H Me 2 —CO—(CH₂)₄-(3-CF₃-Ph) H H 1-2339 H H H Me 2—CO—(CH₂)₄-(3,4-diCF₃-Ph) H H 1-2340 H H H Me 2—CO—(CH₂)₄-(3,5-diCF₃-Ph) H H 1-2341 H H H Me 2 —CO—(CH₂)₄-(3-MeO-Ph) HH 1-2342 H H H Me 2 —CO—(CH₂)₄-(3,4-diMeO-Ph) H H 1-2343 H H H Me 2—CO—(CH₂)₄-(3,5-diMeO-Ph) H H 1-2344 H H H Me 2—CO—(CH₂)₄-(3,4,5-triMeO-Ph) H H 1-2345 H H H Me 2 —CO—(CH₂)₄-(3-Ac-Ph)H H 1-2346 H H H Me 2 —CO—(CH₂)₄-(4-Ac-Ph) H H 1-2347 H H H Me 2—CH(OH)—(CH₂)₃-(3-F-Ph) H H 1-2348 H H H Me 2 —CH(OH)—(CH₂)₃-(4-F-Ph) HH 1-2349 H H H Me 2 —CH(OH)—(CH₂)₃-(3,4-diF-Ph) H H 1-2350 H H H Me 2—CH(OH)—(CH₂)₃-(3,5-diF-Ph) H H 1-2351 H H H Me 2—CH(OH)—(CH₂)₃-(3-Cl-Ph) H H 1-2352 H H H Me 2 —CH(OH)—(CH₂)₃-(4-Cl-Ph)H H 1-2353 H H H Me 2 —CH(OH)—(CH₂)₃-(3,4-diCl-Ph) H H 1-2354 H H H Me 2—CH(OH)—(CH₂)₃-(3,5-diCl-Ph) H H 1-2355 H H H Me 2—CH(OH)—(CH₂)₃-(3-Me-Ph) H H 1-2356 H H H Me 2 —CH(OH)—(CH₂)₃-(4-Me-Ph)H H 1-2357 H H H Me 2 —CH(OH)—(CH₂)₃-(3,4-diMe-Ph) H H 1-2358 H H H Me 2—CH(OH)—(CH₂)₃-(3,5-diMe-Ph) H H 1-2359 H H H Me 2—CH(OH)—(CH₂)₃-(3-Et-Ph) H H 1-2360 H H H Me 2 —CH(OH)—(CH₂)₃-(4-Et-Ph)H H 1-2361 H H H Me 2 —CH(OH)—(CH₂)₃-(3-CF₃-Ph) H H 1-2362 H H H Me 2—CH(OH)—(CH₂)₃-(4-CF₃-Ph) H H 1-2363 H H H Me 2—CH(OH)—(CH₂)₃-(3,4-diCF₃-Ph) H H 1-2364 H H H Me 2—CH(OH)—(CH₂)₃-(3,5-diCF₃-Ph) H H 1-2365 H H H Me 2—CH(OH)—(CH₂)₃-(3-MeO-Ph) H H 1-2366 H H H Me 2—CH(OH)—(CH₂)₃-(4-MeO-Ph) H H 1-2367 H H H Me 2—CH(OH)—(CH₂)₃-(3,4-diMeO-Ph) H H 1-2368 H H H Me 2—CH(OH)—(CH₂)₃-(3,5-diMeO-Ph) H H 1-2369 H H H Me 2—CH(OH)—(CH₂)₃-(3,4,5-triMeO-Ph) H H 1-2370 H H H Me 2—CH(OH)—(CH₂)₃-(4-MeS-Ph) H H 1-2371 H H H Me 2 —CH(OH)—(CH₂)₃-(3-Ac-Ph)H H 1-2372 H H H Me 2 —CH(OH)—(CH₂)₃-(4-Ac-Ph) H H 1-2373 H H H Me 2—CH(OH)—(CH₂)₄-(3-F-Ph) H H 1-2374 H H H Me 2—CH(OH)—(CH₂)₄-(3,4-diF-Ph) H H 1-2375 H H H Me 2—CH(OH)—(CH₂)₄-(3,5-diF-Ph) H H 1-2376 H H H Me 2—CH(OH)—(CH₂)₄-(3-Cl-Ph) H H 1-2377 H H H Me 2 —CH(OH)—(CH₂)₄-(4-Cl-Ph)H H 1-2378 H H H Me 2 —CH(OH)—(CH₂)₄-(3,4-diCl-Ph) H H 1-2379 H H H Me 2—CH(OH)—(CH₂)₄-(3,5-diCl-Ph) H H 1-2380 H H H Me 2—CH(OH)—(CH₂)₄-(3-Me-Ph) H H 1-2381 H H H Me 2—CH(OH)—(CH₂)₄-(3,4-diMe-Ph) H H 1-2382 H H H Me 2—CH(OH)—(CH₂)₄-(3,5-diMe-Ph) H H 1-2383 H H H Me 2—CH(OH)—(CH₂)₄-(3-CF₃-Ph) H H 1-2384 H H H Me 2—CH(OH)—(CH₂)₄-(3,4-diCF₃-Ph) H H 1-2385 H H H Me 2—CH(OH)—(CH₂)₄-(3,5-diCF₃-Ph) H H 1-2386 H H H Me 2—CH(OH)—(CH₂)₄-(3-MeO-Ph) H H 1-2387 H H H Me 2—CH(OH)—(CH₂)₄-(3,4-diMeO-Ph) H H 1-2388 H H H Me 2—CH(OH)—(CH₂)₄-(3,5-diMeO-Ph) H H 1-2389 H H H Me 2—CH(OH)—(CH₂)₄-(3,4,5-triMeO-Ph) H H 1-2390 H H H Me 2—CH(OH)—(CH₂)₄-(3-Ac-Ph) H H 1-2391 H H H Me 2 —CH(OH)—(CH₂)₄-(4-Ac-Ph)H H 1-2392 H H H Me 2 —O—(CH₂)₃-cHx H H 1-2393 H H H Me 2 —O—(CH₂)₄-cHxH H 1-2394 H H H Me 2 —O—(CH₂)₅-cHx H H 1-2395 H H H Me 2 —O—(CH₂)₃-Ph HH 1-2396 H H H Me 2 —O—(CH₂)₄-Ph H H 1-2397 H H H Me 2 —O—(CH₂)₅-Ph H H

[0269] TABLE 2 (Ib)

Exemp. Compd. No. R¹ R² R³ R⁴ n —X—Y—R⁵ R⁶ R⁷ 2-1 H H H Me 1 —(CH₂)₅—cHxH H 2-2 H H H Me 1 —(CH₂)₆—cHx H H 2-3 H H H Me 1 —C≡C—(CH₂)₃—cHx H H2-4 H H H Me 1 —C≡C—(CH₂)₄—cHx H H 2-5 H H H Me 1 -4-(cHx—CH₂O)Ph H H2-6 H H H Me 1 -(4-BzO—Ph) H H 2-7 H H H Me 1 —C≡C—(CH₂)₂O—cHx H H 2-8 HH H Me 1 —C≡C—(CH₂)₂O—Ph H H 2-9 H H H Me 2 —(CH₂)₃—cHx H H 2-10 H H HMe 2 —(CH₂)₃—Ph H H 2-11 H H H Me 2 —(CH₂)₄—cHx H H 2-12 H H H Me 2—(CH₂)₄—Ph H H 2-13 H H H Me 2 —(CH₂)₅—cPn H H 2-14 H H H Me 2—(CH₂)₅—cHx H H 2-15 H H H Me 2 —(CH₂)₅—cHx Me H 2-16 H H H Me 2—(CH₂)₅—cHx H Me 2-17 H H H Me 2 —(CH₂)₅—cHx F H 2-18 H H H Me 2—(CH₂)₅—cHx H F 2-19 H H Me Me 2 —(CH₂)₅—cHx H H 2-20 Me H H Me 2—(CH₂)₅—cHx H H 2-21 CO₂Me H H Me 2 —(CH₂)₅—cHx H H 2-22 H H H Me 2—(CH₂)₅-(4-F—cHx) H H 2-23 H H H Me 2 —(CH₂)₅-(4-Cl—cHx) H H 2-24 H H HMe 2 —(CH₂)₅-(4-Br—cHx) H H 2-25 H H H Me 2 —(CH₂)₅-(4-Me—cHx) H H 2-26H H H Me 2 —(CH₂)₅-(4-Et—cHx) H H 2-27 H H H Me 2 —(CH₂)₅-(4-Pr—cHx) H H2-28 H H H Me 2 —(CH₂)₅-(4-iPr—cHx) H H 2-29 H H H Me 2—(CH₂)₅-(4-CF₃—cHx) H H 2-30 H H H Me 2 —(CH₂)₅-(4-MeO—cHx) H H 2-31 H HH Me 2 —(CH₂)₅-(4-EtO—cHx) H H 2-32 H H H Me 2 —(CH₂)₅-(4-PrO—cHx) H H2-33 H H H Me 2 —(CH₂)₅-(4-iPrO—cHx) H H 2-34 H H H Me 2—(CH₂)₅-(3-MeS—cHx) H H 2-35 H H H Me 2 —(CH₂)₅-(4-MeS—cHx) H H 2-36 H HH Me 2 —(CH₂)₅-(2,4-diMe—cHx) H H 2-37 H H H Me 2 —(CH₂)₅-(3,4-diMe—cHx)H H 2-38 H H H Me 2 —(CH₂)₅-(3,5-diMe—cHx) H H 2-39 H H H Me 2—(CH₂)₅—Ph H H 2-40 H H H Me 2 —(CH₂)₅—Ph Me H 2-41 H H H Me 2—(CH₂)₅—Ph H Me 2-42 H H H Me 2 —(CH₂)₅—Ph F H 2-43 H H H Me 2—(CH₂)₅—Ph H F 2-44 H H Me Me 2 —(CH₂)₅—Ph H H 2-45 Me H H Me 2—(CH₂)₅—Ph H H 2-46 CO₂Me H H Me 2 —(CH₂)₅—Ph H H 2-47 H H H Me 2—(CH₂)₅-(4-F—Ph) H H 2-48 H H H Me 2 —(CH₂)₅-(4-Cl—Ph) H H 2-49 H H H Me2 —(CH₂)₅-(4-Br—Ph) H H 2-50 H H H Me 2 —(CH₂)₅-(4-Me—Ph) H H 2-51 H H HMe 2 —(CH₂)₅-(4-Et—Ph) H H 2-52 H H H Me 2 —(CH₂)₅-(4-Pr—Ph) H H 2-53 HH H Me 2 —(CH₂)₅-(4-iPr—Ph) H H 2-54 H H H Me 2 —(CH₂)₅-(4-Bu—Ph) H H2-55 H H H Me 2 —(CH₂)₅-(4-CF₃—Ph) H H 2-56 H H H Me 2—(CH₂)₅-(4-MeO—Ph) H H 2-57 H H H Me 2 —(CH₂)₅-(4-EtO—Ph) H H 2-58 H H HMe 2 —(CH₂)₅-(4-PrO—Ph) H H 2-59 H H H Me 2 —(CH₂)₅-(4-iPrO—Ph) H H 2-60H H H Me 2 —(CH₂)₅-(3-MeS—Ph) H H 2-61 H H H Me 2 —(CH₂)₅-(4-MeS—Ph) H H2-62 H H H Me 2 —(CH₂)₅-(2,4-diMe—Ph) H H 2-63 H H H Me 2—(CH₂)₅-(3,4-diMe—Ph) H H 2-64 H H H Me 2 —(CH₂)₅-(3,5-diMe—Ph) H H 2-65H H H Me 2 —(CH₂)₆—cPn H H 2-66 H H H Me 2 —(CH₂)₆—cHx H H 2-67 H H H Me2 —(CH₂)₆—cHx Me H 2-68 H H H Me 2 —(CH₂)₆—cHx H Me 2-69 H H H Me 2—(CH₂)₆—cHx F H 2-70 H H H Me 2 —(CH₂)₆—cHx H F 2-71 H H Me Me 2—(CH₂)₆—cHx H H 2-72 Me H H Me 2 —(CH₂)₆—cHx H H 2-73 CO₂Me H H Me 2—(CH₂)₆—cHx H H 2-74 H H H Me 2 —(CH₂)₆-(4-F—cHx) H H 2-75 H H H Me 2—(CH₂)₆-(4-Cl—cHx) H H 2-76 H H H Me 2 —(CH₂)₆-(4-Br—cHx) H H 2-77 H H HMe 2 —(CH₂)₆-(4-Me—cHx) H H 2-78 H H H Me 2 —(CH₂)₆-(4-Et—cHx) H H 2-79H H H Me 2 —(CH₂)₆-(4-Pr—cHx) H H 2-80 H H H Me 2 —(CH₂)₆-(4-iPr—cHx) HH 2-81 H H H Me 2 —(CH₂)₆-(4-Bu—cHx) H H 2-82 H H H Me 2—(CH₂)₆-(4-CF₃—cHx) H H 2-83 H H H Me 2 —(CH₂)₆-(4-MeO—cHx) H H 2-84 H HH Me 2 —(CH₂)₆-(4-EtO—cHx) H H 2-85 H H H Me 2 —(CH₂)₆-(4-PrO—cHx) H H2-86 H H H Me 2 —(CH₂)₆-(4-iPrO—cHx) H H 2-87 H H H Me 2—(CH₂)₆-(3-MeS—cHx) H H 2-88 H H H Me 2 —(CH₂)₆-(4-MeS—cHx) H H 2-89 H HH Me 2 —(CH₂)₆-(2,4-diMe—cHx) H H 2-90 H H H Me 2 —(CH₂)₆-(3,4-diMe—cHx)H H 2-91 H H H Me 2 —(CH₂)₆-(3,5-diMe—cHx) H H 2-92 H H H Me 2—(CH₂)₆—Ph H H 2-93 H H H Me 2 —(CH₂)₆—Ph Me H 2-94 H H H Me 2—(CH₂)₆—Ph H Me 2-95 H H H Me 2 —(CH₂)₆—Ph F H 2-96 H H H Me 2—(CH₂)₆—Ph H F 2-97 H H Me Me 2 —(CH₂)₆—Ph H H 2-98 Me H H Me 2—(CH₂)₆—Ph H H 2-99 CO₂Me H H Me 2 —(CH₂)₆—Ph H H 2-100 H H H Me 2—(CH₂)₆-(4-F—Ph) H H 2-101 H H H Me 2 —(CH₂)₆-(4-Cl—Ph) H H 2-102 H H HMe 2 —(CH₂)₆-(4-Br—Ph) H H 2-103 H H H Me 2 —(CH₂)₆-(4-Me—Ph) H H 2-104H H H Me 2 —(CH₂)₆-(4-Et—Ph) H H 2-105 H H H Me 2 —(CH₂)₆-(4-Pr—Ph) H H2-106 H H H Me 2 —(CH₂)₆-(4-iPr—Ph) H H 2-107 H H H Me 2—(CH₂)₆-(4-Bu—Ph) H H 2-108 H H H Me 2 —(CH₂)₆-(4-CF₃—Ph) H H 2-109 H HH Me 2 —(CH₂)₆-(4-MeO—Ph) H H 2-110 H H H Me 2 —(CH₂)₆-(4-EtO—Ph) H H2-111 H H H Me 2 —(CH₂)₆-(4-PrO—Ph) H H 2-112 H H H Me 2—(CH₂)₆-(4-iPrO—Ph) H H 2-113 H H H Me 2 —(CH₂)₆-(3-MeS—Ph) H H 2-114 HH H Me 2 —(CH₂)₆-(4-MeS—Ph) H H 2-115 H H H Me 2 —(CH₂)₆-(2,4-diMe—Ph) HH 2-116 H H H Me 2 —(CH₂)₆-(3,4-diMe—Ph) H H 2-117 H H H Me 2—(CH₂)₆-(3,5-diMe—Ph) H H 2-118 H H H Me 2 —(CH₂)₇—cHx H H 2-119 H H HMe 2 —(CH₂)₇—Ph H H 2-120 H H H Me 2 —(CH₂)₈—cHx H H 2-121 H H H Me 2—(CH₂)₈—Ph H H 2-122 H H H Me 2 —CH═CH—(CH₂)₃—cHx H H 2-123 H H Me Me 2—CH═CH—(CH₂)₃—cHx H H 2-124 Me H H Me 2 —CH═CH—(CH₂)₃—cHx H H 2-125CO₂Me H H Me 2 —CH═CH—(CH₂)₃—cHx H H 2-126 H H H Me 2 —CH═CH—(CH₂)₃—Ph HH 2-127 H H Me Me 2 —CH═CH—(CH₂)₃—Ph H H 2-128 Me H H Me 2—CH═CH—(CH₂)₃—Ph H H 2-129 CO₂Me H H Me 2 —CH═CH—(CH₂)₃—Ph H H 2-130 H HH Me 2 —CH═CH—(CH₂)₄—cHx H H 2-131 H H Me Me 2 —CH═CH—(CH₂)₄—cHx H H2-132 Me H H Me 2 —CH═CH—(CH₂)₄—cHx H H 2-133 CO₂Me H H Me 2—CH═CH—(CH₂)₄—cHx H H 2-134 H H H Me 2 —CH═CH—(CH₂)₄—Ph H H 2-135 H H MeMe 2 —CH═CH—(CH₂)₄—Ph H H 2-136 Me H H Me 2 —CH═CH—(CH₂)₄—Ph H H 2-137CO₂Me H H Me 2 —CH═CH—(CH₂)₄—Ph H H 2-138 H H H Me 2 —C═C—CH₂O—cHx H H2-139 H H H Me 2 —C═C—CH₂O—Ph H H 2-140 H H H Me 2 —C═C—(CH₂)₂O—cHx H H2-141 H H H Me 2 —C═C—(CH₂)₂O—Ph H H 2-142 H H H Me 2 —C≡C—CH₂—cHx H H2-143 H H Me Me 2 —C≡C—CH₂—cHx H H 2-144 Me H H Me 2 —C≡C—CH₂—cHx H H2-145 CO₂Me H H Me 2 —C≡C—CH₂—cHx H H 2-146 H H H Me 2 —C≡C—CH₂—Ph H H2-147 H H Me Me 2 —C≡C—CH₂—Ph H H 2-148 Me H H Me 2 —C≡C—CH₂—Ph H H2-149 CO₂Me H H Me 2 —C≡C—CH₂—Ph H H 2-150 H H H Me 2 —C≡C—(CH₂)₂—cHx HH 2-151 H H Me Me 2 —C≡C—(CH₂)₂—cHx H H 2-152 Me H H Me 2—C≡C—(CH₂)₂—cHx H H 2-153 CO₂Me H H Me 2 —C≡C—(CH₂)₂—cHx H H 2-154 H H HMe 2 —C≡C—(CH₂)₂—Ph H H 2-155 H H Me Me 2 —C≡C—(CH₂)₂—Ph H H 2-156 Me HH Me 2 —C≡C—(CH₂)₂—Ph H H 2-157 CO₂Me H H Me 2 —C≡C—(CH₂)₂—Ph H H 2-158H H H Me 2 —C≡C—(CH₂)₃—cPn H H 2-159 H H H Me 2 —C≡C—(CH₂)₃—cHx H H2-160 H H H Me 2 —C≡C—(CH₂)₃—cHx Me H 2-161 H H H Me 2 —C≡C—(CH₂)₃—cHx HMe 2-162 H H H Me 2 —C≡C—(CH₂)₃—cHx F H 2-163 H H H Me 2 —C≡C—(CH₂)₃—cHxH F 2-164 H H Me Me 2 —C≡C—(CH₂)₃—cHx H H 2-165 Me H H Me 2—C≡C—(CH₂)₃—cHx H H 2-166 CO₂Me H H Me 2 —C≡C—(CH₂)₃—cHx H H 2-167 H H HMe 2 —C≡C—(CH₂)₃-(4-F—cHx) H H 2-168 H H H Me 2 —C≡C—(CH₂)₃-(4-Cl—cHx) HH 2-169 H H H Me 2 —C≡C—(CH₂)₃-(4-Br—cHx) H H 2-170 H H H Me 2—C≡C—(CH₂)₃-(4-Me—cHx) H H 2-171 H H H Me 2 —C≡C—(CH₂)₃-(4-Et—cHx) H H2-172 H H H Me 2 —C≡C—(CH₂)₃-(4-Pr—cHx) H H 2-173 H H H Me 2—C≡C—(CH₂)₃-(4-iPr—cHx) H H 2-174 H H H Me 2 —C≡C—(CH₂)₃-(4-Bu—cHx) H H2-175 H H H Me 2 —C≡C—(CH₂)₃-(4-CF₃—cHx) H H 2-176 H H H Me 2—C≡C—(CH₂)₃-(4-MeO—cHx) H H 2-177 H H H Me 2 —C≡C—(CH₂)₃-(4-EtO—cHx) H H2-178 H H H Me 2 —C≡C—(CH₂)₃-(4-PrO—cHx) H H 2-179 H H H Me 2—C≡C—(CH₂)₃-(4-iPrO—cHx) H H 2-180 H H H Me 2 —C≡C—(CH₂)₃-(3-MeS—cHx) HH 2-181 H H H Me 2 —C≡C—(CH₂)₃-(4-MeS—cHx) H H 2-182 H H H Me 2—C≡C—(CH₂)₃-(2,4-diMe—cHx) H H 2-183 H H H Me 2—C≡C—(CH₂)₃-(3,4-diMe—cHx) H H 2-184 H H H Me 2—C≡C—(CH₂)₃-(3,5-diMe—cHx) H H 2-185 H H H Me 2 —C≡C—(CH₂)₃—Ph H H 2-186H H H Me 2 —C≡C—(CH₂)₃—Ph Me H 2-187 H H H Me 2 —C≡C—(CH₂)₃—Ph H Me2-188 H H H Me 2 —C≡C—(CH₂)₃—Ph F H 2-189 H H H Me 2 —C≡C—(CH₂)₃—Ph H F2-190 H H Me Me 2 —C≡C—(CH₂)₃—Ph H H 2-191 Me H H Me 2 —C≡C—(CH₂)₃—Ph HH 2-192 CO₂Me H H Me 2 —C≡C—(CH₂)₃—Ph H H 2-193 H H H Me 2—C≡C—(CH₂)₃-(4-F—Ph) H H 2-194 H H H Me 2 —C≡C—(CH₂)₃-(4-Cl—Ph) H H2-195 H H H Me 2 —C≡C—(CH₂)₃-(4-Br—Ph) H H 2-196 H H H Me 2—C≡C—(CH₂)₃-(4-Me—Ph) H H 2-197 H H H Me 2 —C≡C—(CH₂)₃-(4-Et—Ph) H H2-198 H H H Me 2 —C≡C—(CH₂)₃-(4-Pr—Ph) H H 2-199 H H H Me 2—C≡C—(CH₂)₃-(4-iPr—Ph) H H 2-200 H H H Me 2 —C≡C—(CH₂)₃-(4-Bu—Ph) H H2-201 H H H Me 2 —C≡C—(CH₂)₃-(4-CF₃—Ph) H H 2-202 H H H Me 2—C≡C—(CH₂)₃-(4-MeO—Ph) H H 2-203 H H H Me 2 —C≡C—(CH₂)₃-(4-EtO—Ph) H H2-204 H H H Me 2 —C≡C—(CH₂)₃-(4-PrO—Ph) H H 2-205 H H H Me 2—C≡C—(CH₂)₃-(4-iPrO—Ph) H H 2-206 H H H Me 2 —C≡C—(CH₂)₃-(3-MeS—Ph) H H2-207 H H H Me 2 —C≡C—(CH₂)₃-(4-MeS—Ph) H H 2-208 H H H Me 2—C≡C—(CH₂)₃-(2,4-diMe—Ph) H H 2-209 H H H Me 2 —C≡C—(CH₂)₃-(3,4-diMe—Ph)H H 2-210 H H H Me 2 —C≡C—(CH₂)₃-(3,5-diMe—Ph) H H 2-211 H H H Me 2—C≡C—(CH₂)₄—cPn H H 2-212 H H H Me 2 —C≡C—(CH₂)₄—cHx H H 2-213 H H H Me2 —C≡C—(CH₂)₄—cHx Me H 2-214 H H H Me 2 —C≡C—(CH₂)₄—cHx H Me 2-215 H H HMe 2 —C≡C—(CH₂)₄—cHx F H 2-216 H H H Me 2 —C≡C—(CH₂)₄—cHx H F 2-217 H HMe Me 2 —C≡C—(CH₂)₄—cHx H H 2-218 Me H H Me 2 —C≡C—(CH₂)₄—cHx H H 2-219CO₂Me H H Me 2 —C≡C—(CH₂)₄—cHx H H 2-220 H H H Me 2—C≡C—(CH₂)₄-(4-F—cHx) H H 2-221 H H H Me 2 —C≡C—(CH₂)₄-(4-Cl—cHx) H H2-222 H H H Me 2 —C≡C—(CH₂)₄-(4-Br—cHx) H H 2-223 H H H Me 2—C≡C—(CH₂)₄-(4-Me—cHx) H H 2-224 H H H Me 2 —C≡C—(CH₂)₄-(4-Et—cHx) H H2-225 H H H Me 2 —C≡C—(CH₂)₄-(4-Pr—cHx) H H 2-226 H H H Me 2—C≡C—(CH₂)₄-(4-iPr—cHx) H H 2-227 H H H Me 2 —C≡C—(CH₂)₄-(4-Bu—cHx) H H2-228 H H H Me 2 —C≡C—(CH₂)₄-(4-CF₃—cHx) H H 2-229 H H H Me 2—C≡C—(CH₂)₄-(4-MeO—cHx) H H 2-230 H H H Me 2 —C≡C—(CH₂)₄-(4-EtO—cHx) H H2-231 H H H Me 2 —C≡C—(CH₂)₄-(4-PrO—cHx) H H 2-232 H H H Me 2—C≡C—(CH₂)₄-(4-iPrO—cHx) H H 2-233 H H H Me 2 —C≡C—(CH₂)₄-(4-MeS—cHx) HH 2-234 H H H Me 2 —C≡C—(CH₂)₄-(2,4-diMe—cHx) H H 2-235 H H H Me 2—C≡C—(CH₂)₄-(3,4-diMe—cHx) H H 2-236 H H H Me 2—C≡C—(CH₂)₄-(3,5-diMe—cHx) H H 2-237 H H H Me 2 —C≡C—(CH₂)₄—Ph H H 2-238H H H Me 2 —C≡C—(CH₂)₄—Ph Me H 2-239 H H H Me 2 —C≡C—(CH₂)₄—Ph H Me2-240 H H H Me 2 —C≡C—(CH₂)₄—Ph F H 2-241 H H H Me 2 —C≡C—(CH₂)₄—Ph H F2-242 H H Me Me 2 —C≡C—(CH₂)₄—Ph H H 2-243 Me H H Me 2 —C≡C—(CH₂)₄—Ph HH 2-244 CO₂Me H H Me 2 —C≡C—(CH₂)₄—Ph H H 2-245 H H H Me 2—C≡C—(CH₂)₄-(4-F—Ph) H H 2-246 H H H Me 2 —C≡C—(CH₂)₄-(4-Cl—Ph) H H2-247 H H H Me 2 —C≡C—(CH₂)₄-(4-Br—Ph) H H 2-248 H H H Me 2—C≡C—(CH₂)₄-(4-Me—Ph) H H 2-249 H H H Me 2 —C≡C—(CH₂)₄-(4-Et—Ph) H H2-250 H H H Me 2 —C≡C—(CH₂)₄-(4-Pr—Ph) H H 2-251 H H H Me 2—C≡C—(CH₂)₄-(4-iPr—Ph) H H 2-252 H H H Me 2 —C≡C—(CH₂)₄-(4-Bu—Ph) H H2-253 H H H Me 2 —C≡C—(CH₂)₄-(4-CF₃—Ph) H H 2-254 H H H Me 2—C≡C—(CH₂)₄-(4-MeO—Ph) H H 2-255 H H H Me 2 —C≡C—(CH₂)₄-(4-EtO—Ph) H H2-256 H H H Me 2 —C≡C—(CH₂)₄-(4-PrO—Ph) H H 2-257 H H H Me 2—C≡C—(CH₂)₄-(4-iPrO—Ph) H H 2-258 H H H Me 2 —C≡C—(CH₂)₄-(3-MeS—Ph) H H2-259 H H H Me 2 —C≡C—(CH₂)₄-(4-MeS—Ph) H H 2-260 H H H Me 2—C≡C—(CH₂)₄-(2,4-diMe—Ph) H H 2-261 H H H Me 2 —C≡C—(CH₂)₄-(3,4-diMe—Ph)H H 2-262 H H H Me 2 —C≡C—(CH₂)₄-(3,5-diMe—Ph) H H 2-263 H H H Me 2—C≡C—(CH₂)₅—cHx H H 2-264 H H Me Me 2 —C≡C—(CH₂)₅—cHx H H 2-265 Me H HMe 2 —C≡C—(CH₂)₅—cHx H H 2-266 CO₂Me H H Me 2 —C≡C—(CH₂)₅—cHx H H 2-267H H H Me 2 —C≡C—(CH₂)₅—Ph H H 2-268 H H Me Me 2 —C≡C—(CH₂)₅—Ph H H 2-269Me H H Me 2 —C≡C—(CH₂)₅—Ph H H 2-270 CO₂Me H H Me 2 —C≡C—(CH₂)₅—Ph H H2-271 H H H Me 2 —C≡C—(CH₂)₆—cHx H H 2-272 H H Me Me 2 —C≡C—(CH₂)₆—cHx HH 2-273 Me H H Me 2 —C≡C—(CH₂)₆—cHx H H 2-274 CO₂Me H H Me 2—C≡C—(CH₂)₆—cHx H H 2-275 H H H Me 2 —C≡C—(CH₂)₆—Ph H H 2-276 H H Me Me2 —C≡C—(CH₂)₆—Ph H H 2-277 Me H H Me 2 —C≡C—(CH₂)₆—Ph H H 2-278 CO₂Me HH Me 2 —C≡C—(CH₂)₆—Ph H H 2-279 H H H Me 2 —C≡C—CH₂O—cHx H H 2-280 H HMe Me 2 —C≡C—CH₂O—cHx H H 2-281 Me H H Me 2 —C≡C—CH₂O—cHx H H 2-282CO₂Me H H Me 2 —C≡C—CH₂O—cHx H H 2-283 H H H Me 2 —C≡C—CH₂O—Ph H H 2-284H H Me Me 2 —C≡C—CH₂O—Ph H H 2-285 Me H H Me 2 —C≡C—CH₂O—Ph H H 2-286CO₂Me H H Me 2 —C≡C—CH₂O—Ph H H 2-287 H H H Me 2 —C≡C—(CH₂)₂O—cPn H H2-288 H H H Me 2 —C≡C—(CH₂)₂O—cHx H H 2-289 H H H Me 2 —C≡C—(CH₂)₂O—cHxMe H 2-290 H H H Me 2 —C≡C—(CH₂)₂O—cHx H Me 2-291 H H H Me 2—C≡C—(CH₂)₂O—cHx F H 2-292 H H H Me 2 —C≡C—(CH₂)₂O—cHx H F 2-293 H H MeMe 2 —C≡C—(CH₂)₂—OCH₂—cHx H H 2-294 Me H H Me 2 —C≡C—(CH₂)₂O—cHx H H2-295 CO₂Me H H Me 2 —C≡C—(CH₂)₂O—cHx H H 2-296 H H H Me 2—C≡C—(CH₂)₂O-(4-F—cHx) H H 2-297 H H H Me 2 —C≡C—(CH₂)₂O-(4-Cl—cHx) H H2-298 H H H Me 2 —C≡C—(CH₂)₂O-(4-Br—cHx) H H 2-299 H H H Me 2—C≡C—(CH₂)₂O-(4-Me—cHx) H H 2-300 H H H Me 2 —C≡C—(CH₂)₂O-(4-Et—cHx) H H2-301 H H H Me 2 —C≡C—(CH₂)₂O-(4-Pr—cHx) H H 2-302 H H H Me 2—C≡C—(CH₂)₂O-(4-iPr—cHx) H H 2-303 H H H Me 2 —C≡C—(CH₂)₂O-(4-Bu—cHx) HH 2-304 H H H Me 2 —C≡C—(CH₂)₂O-(4-CF₃—cHx) H H 2-305 H H H Me 2—C≡C—(CH₂)₂O-(4-MeO—cHx) H H 2-306 H H H Me 2 —C≡C—(CH₂)₂O-(4-EtO—cHx) HH 2-307 H H H Me 2 —C≡C—(CH₂)₂O-(4-PrO—cHx) H H 2-308 H H H Me 2—C≡C—(CH₂)₂O-(4-iPrO—cHx) H H 2-309 H H H Me 2 —C≡C—(CH₂)₂O-(3-MeS—cHx)H H 2-310 H H H Me 2 —C≡C—(CH₂)₂O-(4-MeS—cHx) H H 2-311 H H H Me 2—C≡C—(CH₂)₂O-(2,4-diMe—cHx) H H 2-312 H H H Me 2—C≡C—(CH₂)₂O-(3,4-diMe—cHx) H H 2-313 H H H Me 2—C≡C—(CH₂)₂O-(3,5-diMe—cHx) H H 2-314 H H H Me 2 —C≡C—(CH₂)₂O—Ph H H2-315 H H H Me 2 —C≡C—(CH₂)₂O—Ph Me H 2-316 H H H Me 2 —C≡C—(CH₂)₂O—Ph HMe 2-317 H H H Me 2 —C≡C—(CH₂)₂O—Ph F H 2-318 H H H Me 2 —C≡C—(CH₂)₂O—PhH F 2-319 H H Me Me 2 —C≡C—(CH₂)₂—OCH₂—Ph H H 2-320 Me H H Me 2—C≡C—(CH₂)₂O—Ph H H 2-321 CO₂Me H H Me 2 —C≡C—(CH₂)₂O—Ph H H 2-322 H H HMe 2 —C≡C—(CH₂)₂O-(4-F—Ph) H H 2-323 H H H Me 2 —C≡C—(CH₂)₂O-(4-Cl—Ph) HH 2-324 H H H Me 2 —C≡C—(CH₂)₂O-(4-Br—Ph) H H 2-325 H H H Me 2—C≡C—(CH₂)₂O-(4-Me—Ph) H H 2-326 H H H Me 2 —C≡C—(CH₂)₂O-(4-Et—Ph) H H2-327 H H H Me 2 —C≡C—(CH₂)₂O-(4-Pr—Ph) H H 2-328 H H H Me 2—C≡C—(CH₂)₂O-(4-iPr—Ph) H H 2-329 H H H Me 2 —C≡C—(CH₂)₂O-(4-Bu—Ph) H H2-330 H H H Me 2 —C≡C—(CH₂)₂O-(4-CF₃—Ph) H H 2-331 H H H Me 2—C≡C—(CH₂)₂O-(4-MeO—Ph) H H 2-332 H H H Me 2 —C≡C—(CH₂)₂O-(4-EtO—Ph) H H2-333 H H H Me 2 —C≡C—(CH₂)₂O-(4-PrO—Ph) H H 2-334 H H H Me 2—C≡C—(CH₂)₂O-(4-iPrO—Ph) H H 2-335 H H H Me 2 —C≡C—(CH₂)₂O-(4-MeS—Ph) HH 2-336 H H H Me 2 —C≡C—(CH₂)₂O-(2,4-diMe—Ph) H H 2-337 H H H Me 2—C≡C—(CH₂)₂O-(3,4-diMe—Ph) H H 2-338 H H H Me 2—C≡C—(CH₂)₂O-(3,5-diMe—Ph) H H 2-339 H H H Me 2 —CO—(CH₂)₄—cHx H H 2-340H H Me Me 2 —CO—(CH₂)₄—cHx H H 2-341 Me H H Me 2 —CO—(CH₂)₄—cHx H H2-342 CO₂Me H H Me 2 —CO—(CH₂)₄—cHx H H 2-343 H H H Me 2 —CO—(CH₂)₄—Ph HH 2-344 H H Me Me 2 —CO—(CH₂)₄—Ph H H 2-345 Me H H Me 2 —CO—(CH₂)₄—Ph HH 2-346 CO₂Me H H Me 2 —CO—(CH₂)₄—Ph H H 2-347 H H H Me 2 —CO—(CH₂)₅—cHxH H 2-348 H H Me Me 2 —CO—(CH₂)₅—cHx H H 2-349 Me H H Me 2—CO—(CH₂)₅—cHx H H 2-350 CO₂Me H H Me 2 —CO—(CH₂)₅—cHx H H 2-351 H H HMe 2 —CO—(CH₂)₅—Ph H H 2-352 H H Me Me 2 —CO—(CH₂)₅—Ph H H 2-353 Me H HMe 2 —CO—(CH₂)₅—Ph H H 2-354 CO₂Me H H Me 2 —CO—(CH₂)₅—Ph H H 2-355 H HH Me 2 —CH(OH)—(CH₂)₄—cHx H H 2-356 H H Me Me 2 —CH(OH)—(CH₂)₄—cHx H H2-357 Me H H Me 2 —CH(OH)—(CH₂)₄—cHx H H 2-358 CO₂Me H H Me 2—CH(OH)—(CH₂)₄—cHx H H 2-359 H H H Me 2 —CH(OH)—(CH₂)₄—Ph H H 2-360 H HMe Me 2 —CH(OH)—(CH₂)₄—Ph H H 2-361 Me H H Me 2 —CH(OH)—(CH₂)₄—Ph H H2-362 CO₂Me H H Me 2 —CH(OH)—(CH₂)₄—Ph H H 2-363 H H H Me 2—CH(OH)—(CH₂)₅—cHx H H 2-364 H H Me Me 2 —CH(OH)—(CH₂)₅—cHx H H 2-365 MeH H Me 2 —CH(OH)—(CH₂)₅—cHx H H 2-366 CO₂Me H H Me 2 —CH(OH)—(CH₂)₅—cHxH H 2-367 H H H Me 2 —CH(OH)—(CH₂)₅—Ph H H 2-368 H H Me Me 2—CH(OH)—(CH₂)₅—Ph H H 2-369 Me H H Me 2 —CH(OH)—(CH₂)₅—Ph H H 2-370CO₂Me H H Me 2 —CH(OH)—(CH₂)₅—Ph H H 2-371 H H H Me 2 -4-(cHx—CH₂O)Ph HH 2-372 H H Me Me 2 -4-(cHx—CH₂O)Ph H H 2-373 Me H H Me 2-4-(cHx—CH₂O)Ph H H 2-374 CO₂Me H H Me 2 -4-(cHx—CH₂O)Ph H H 2-375 H H HMe 2 -4-[cHx—(CH₂)₂O]Ph H H 2-376 H H H Me 2 -4-[cHx—(CH₂)₃O]Ph H H2-377 H H H Me 2 -(4-BzO—Ph) H H 2-378 H H Me Me 2 -(4-BzO—Ph) H H 2-379Me H H Me 2 -(4-BzO—Ph) H H 2-380 CO₂Me H H Me 2 -(4-BzO—Ph) H H 2-381 HH H Me 2 -(4-BzO-2-F—Ph) H H 2-382 H H H Me 2 -(4-BzO-3-F—Ph) H H 2-383H H H Me 2 -(4-BzO-2,3-diF—Ph) H H 2-384 H H H Me 2 -(4-BzO-2-Cl—Ph) H H2-385 H H H Me 2 -(4-BzO-3-Cl—Ph) H H 2-386 H H H Me 2-(4-BzO-2,3-diCl—Ph) H H 2-387 H H H Me 2 -(4-BzO-2-Me—Ph) H H 2-388 H HH Me 2 -(4-BzO-3-Me—Ph) H H 2-389 H H H Me 2 -(4-BzO-2,3-diMe—Ph) H H2-390 H H H Me 2 -4-[Ph—(CH₂)₂O]—Ph H H 2-391 H H H Me 2-4-[Ph—(CH₂)₃O]—Ph H H 2-392 H H H Et 2 —(CH₂)₅—cHx H H 2-393 H H H Et 2—(CH₂)₆—cHx H H 2-394 H H H Et 2 —C≡C—(CH₂)₃—cHx H H 2-395 H H H Et 2—C≡C—(CH₂)₄—cHx H H 2-396 H H H Et 2 -4-(cHx—CH₂O)Ph H H 2-397 H H H Et2 -(4-BzO—Ph) H H 2-398 H H H Et 2 —C≡C—(CH₂)₂O—cHx H H 2-399 H H H Et 2—C≡C—(CH₂)₂O—Ph H H 2-400 H H H Pr 2 —(CH₂)₅—cHx H H 2-401 H H H Pr 2—(CH₂)₆—cHx H H 2-402 H H H Pr 2 —C≡C—(CH₂)₃—cHx H H 2-403 H H H Pr 2—C≡C—(CH₂)₄—cHx H H 2-404 H H H Pr 2 -4-(cHx—CH₂O)Ph H H 2-405 H H H Pr2 -(4-BzO—Ph) H H 2-406 H H H Pr 2 —C≡C—(CH₂)₂O—cHx H H 2-407 H H H Pr 2—C≡C—(CH₂)₂O—Ph H H 2-408 H H H Me 3 —(CH₂)₅—cHx H H 2-409 H H H Me 3—(CH₂)₆—cHx H H 2-410 H H H Me 3 —C≡C—(CH₂)₃—cHx H H 2-411 H H H Me 3—C≡C—(CH₂)₄—cHx H H 2-412 H H H Me 3 -4-(cHx—CH₂O)Ph H H 2-413 H H H Me3 -(4-BzO—Ph) H H 2-414 H H H Me 3 —C≡C—(CH₂)₂O—cHx H H 2-415 H H H Me 3—C≡C—(CH₂)₂O—Ph H H

[0270] Preferred compounds in Tables 1 to 2 are those of Exemplificationcompounds numbers 1-19, 1-23 to 1-32, 1-36 to 1-45, 1-49 to 1-58, 1-62to 1-71, 1-75 to 1-84, 1-88 to 1-102, 1-106 to 1-156, 1-160 to 1-214,1-218 to 1-268, 1-272 to 1-322, 1-325 to 1-334, 1-338 to 1-347, 1-360,1-364 to 1-372, 1-377 to 1-386, 1-390 to 1-404, 1-408 to 1-458, 1-462 to1-513, 1-517 to 1-526, 1-530 to 1-544, 1-548 to 1-598, 1-602 to 1-657,1-670, 1-674 to 1-683, 1-696, 1-700 to 1-717, 1-721 to 1-730, 1-734 to1-743, 1-747 to 1-756, 1-760 to 1-774, 1-778 to 1-828, 1-832 to 1-886,1-890 to 1-940, 1-944 to 1-993, 1-997 to 1-1006, 1-1010 to 1-1019,1-1045, 1-1049 to 1-1058, 1-1062 to 1-1076, 1-1080 to 1-1130, 1-1-1134to 1-1185, 1-1189 to 1-1198, 1-1202 to 1-1208, 1-1212 to 1-1216, 1-1220to 1-1270, 1-1274 to 1-1331, 1-1335 to 1-1344, 1-1348 to 1-1357, 1-1361to 1-1370, 1-1374 to 1-1387, 1-1391 to 1-1400, 1-1404 to 1-1418, 1-1422to 1-1472, 1-1476 to 1-1527, 1-1531 to 1-1540, 1-1544 to 1-1558, 1-1562to 1-1612, 1-1616 to 1-1673, 1-1677 to 1-1686, 1-1690 to 1-1699, 1-1703to 1-1712, 1-1716 to 1-1729, 1-1733 to 1-1744, 1-1748 to 1-1767, 1-1772to 1-1793, 1-1797 to 1-1818, 1-1824 to 1-1846, 1-1850 to 1-1869, 1-1872,1-1876, 1-1880, 1-1884, 1-1888 to 1-1892, 1-1896, 1-1900, 1-1908 to1-1913, 1-1917 to 1-1939, 1-1943 to 1-1966, 1-1970 to 1-1991, 1-1995 to1-2013, 1-2017, 1-2021, 1-2025, 1-2029, 1-2033, 1-2037 to 1-2042, 1-2045to 1-2068, 1-2072 to 1-2089, 1-2093, 1-2097, 1-2101, 1-2105, 1-2109,1-2113, 1-2117, 1-2121, 1-2125, 1-2129, 1-2133, 1-2135, 1-2139 to1-2158, 1-2161 to 1-2164, 1-2184 to 1-2346,

[0271]2-9 to 2-18, 2-22 to 2-43, 2-47 to 2-70, 2-74 to 2-96, 2-100 to2-119, 2-142, 2-146, 2-150, 2-154, 2-158 to 2-163, 2-167 to 2-183, 2-185to 2-189, 2-193 to 2-216, 2-220 to 2-241, 2-245 to 2-263, 2-267, 2-271,2-275, 2-279, 2-283, 2-287 to 2-292, 2-296 to 2-318, 2-322 to 2-338,2-343, 2-347, 2-351, 2-371, 2-375 to 2-377, 2-381 to 2-407.

[0272] More preferred compounds are those of Exemplification compoundsnumbers 1-19, 1-32, 1-36 to 1-45, 1-57, 1-62 to 1-71, 1-84, 1-88, 1-97to 1-100, 1-152 to 1-154, 1-160 to 1-214, 1-218 to 1-227, 1-264 to1-268, 1-272 to 1-322, 1-344, 1-347, 1-360, 1-373, 1-386, 1-390 to1-402, 1-454 to 1-458, 1-462 to 1-513, 1-526, 1-530 to 1-542, 1-594 to1-598, 1-602 to 1-653, 1-743, 1-756, 1-760 to 1-768, 1-770 to 1-774,1,-778 to 1-828, 1-832 to 1-886, 1-890 to 1-940, 1-944 to 1-993, 1-1045,1-1058, 1-1062 to 1-1074, 1-1126 to 1-1130, 1-1134 to 1-1185, 1-1198,1-1202 to -1208, 1-1212, 1-1213, 1-1214, 1-1266 to 1270, 1-1274 to 1331,1-1344, 1-1348 to 1-1357, 1-1370, 1-1374 to 1-1387, 1-1400, 1-1404 to1-1416, 1-1468 to 1-1472, 1-1476 to 1-1527, 1-1540, 1-1544 to 1-1556,1-1608 to 1-1612, 1-1616 to 1-1666, 1-1729, 1-1742, 1-1744, 1-1759 to1-1767, 1-1789 to 1-1793, 1-1797 to 1-1818, 1-1842 to 1-1846, 1-1900,1-1908 to 1-1913, 1-1935 to 1-1939, 1-1943 to 1-1966, 1-1987 to 1-1991,1-2013, 1-2017, 1-2029, 1-2033, 1-2037 to 1-2042, 1-2064 to 1-2068,1-2072 to 1-2089, 1-2093, 1-2097, 1-2101, 1-2105, 1-2109, 1-2129,1-2133, 1-2135, 1-2184 to 1-2346,

[0273]2-11 to 2-18, 2-39 to 2-43, 2-47 to 2-70, 2-185 to 2-189, 2-193 to2-216, 2-287 to 2-292, 2-338, 2-343, 2-347, 2-351.

[0274] More preferred compounds are those of Exemplification compoundsnumbers 1-45, 1-71, 1-84, 1-88, 1-97 to 1-100, 1-152 to 1-154, 1-160 to1-206, 1-209 to 1-212, 1-264 to 1-266, 1-334, 1-373, 1-386, 1-390 to1-402, 1-454 to 1-458, 1-462 to 1-485, 1-509, 1-510, 1-513, 1-526, 1-530to 1-542, 1-594-to 1-598, 1-602 to 1-613, 1-649, 1-650, 1-743, 1-756,1-760 to 1-768, 1-770 to 1-772, 1-824 to 1-828, 1-832 to 1-884, 1-936,1-1045, 1-1058, 1-1062 to 1-1074, 1-1126 to 1-1130, 1-1134 to 1-1145,1-1148 to 1-1151, 1-1162, 1-1163, 1-1179 to 1-1182, 1-1185, 1-1198,1-1202 to 1-1208, 1-1212, 1-1213, 1-1214, 1-1266 to 1-1270, 1-1274 to1-1285, 1-1288 to 1-1291, 1-1319 to 1-1322, 1-1329 to 1-1331, 1-1344,1-1348 to 1-1357, 1-1370, 1-1387, 1-1400, 1-1404 to 1-1416, 1-1468 to1-1472, 1-1476 to 1-1487, 1-1490 to 1-1493, 1-1504, 1-1505, 1-1521 to1-1524, 1-1527, 1-1540, 1-1544 to 1-1556, 1-1608 to 1-1612, 1-1616 to1-1627, 1-1663, 1-1664, 1-1729, 1-1742, 1-1744, 1-1761 to 1-1766, 1-1789to 1-1791, 1-1815 to 1-1818, 1-1900, 1-1909, 1-1962, 1-2064 to 1-2066,1-2089, 1-2093, 1-2097, 1-2105, 1-2133, 1-2216 to 1-2288, 1-2290 to1-2346.

[0275] Still more preferred compounds in Tables 1 and 2 are thoseexemplification compounds numbers:

[0276] 1-71:2-amino-2-methyl-4-[5-(4-cyclohexylbutyl)thiophen-2-yl]butan-1-ol,

[0277] 1-84:2-amino-2-methyl-4-[5-(4-phenylbutyl)thiophen-2-yl]butan-1-ol,

[0278] 1-98:2-amino-2-methyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol,

[0279] 1-152:2-amino-2-methyl-4-[5-(5-phenylpentyl)thiophen-2-yl]butan-1-ol,

[0280] 1-210:2-amino-2-methyl-4-[5-(6-cyclohexylhexyl)thiophen-2-yl]butan-1-ol,

[0281] 1-264:2-amino-2-methyl-4-[5-(6-phenylhexyl)thiophen-2-yl]butan-1-ol,

[0282] 1-373:2-amino-2-methyl-4-[5-(3-cyclohexyloxypropyl)thiophen-2-yl]butan-1-ol,

[0283] 1-386:2-amino-2-methyl-4-[5-(3-phenoxypropyl)thiophen-2-yl]butan-1-ol,

[0284] 1-400:2-amino-2-methyl-4-[5-(4-cyclohexyloxybutyl)thiophen-2-yl]butan-1-ol,

[0285] 1-454:2-amino-2-methyl-4-[5-(4-phenoxybutyl)thiophen-2-yl]butan-1-ol,

[0286] 1-509:2-amino-2-methyl-4-[5-(5-cyclohexyloxypentyl)thiophen-2-yl]butan-1-ol,

[0287] 1-510:2-amino-2-methyl-4-[5-(5-phenoxypentyl)thiophen-2-yl]butan-1-ol,

[0288] 1-513:2-amino-2-methyl-4-[5-(3-cyclohexylmethoxypropyl)thiophen-2-yl]butan-1-ol,

[0289] 1-743:2-amino-2-methyl-4-[5-(4-cyclohexylbut-1-ynyl)thiophen-2-yl]butan-1-ol,

[0290] 1-756:2-amino-2-methyl-4-[5-(4-phenylbut-1-ynyl)thiophen-2-yl]butan-1-ol,

[0291] 1-770:2-amino-2-methyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol,

[0292] 1-824:2-amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol,

[0293] 1-882:2-amino-2-methyl-4-[5-(6-cyclohexylhex-1-ynyl)thiophen-2-yl]butan-1-ol,

[0294] 1-936:2-amino-2-methyl-4-[5-(6-phenylhex-1-ynyl)thiophen-2-yl]butan-1-ol,

[0295] 1-1045:2-amino-2-methyl-4-[5-(3-cyclohexyloxypropynyl)thiophen-2-yl]butan-1-ol,

[0296] 1-1058:2-amino-2-methyl-4-[5-(3-phenoxypropynyl)thiophen-2-yl]butan-1-ol,

[0297] 1-1072:2-amino-2-methyl-4-[5-(4-cyclohexyloxybut-1-ynyl)thiophen-2-yl]butan-1-ol,

[0298] 1-1126:2-amino-2-methyl-4-[5-(4-phenoxybut-1-ynyl)thiophen-2-yl]butan-1-ol,

[0299] 1-1181:2-amino-2-methyl-4-[5-(5-cyclohexyloxypent-1-ynyl)thiophen-2-yl]butan-1-ol,

[0300] 1-1182:2-amino-2-methyl-4-[5-(5-phenoxypent-1-ynyl)thiophen-2-yl]butan-1-ol,

[0301] 1-1185:2-amino-2-methyl-4-[5-(3-cyclohexylmethoxypropynyl)thiophen-2-yl]butan-1-ol,

[0302] 1-1329:2-amino-2-methyl-4-[5-(4-cyclohexylbutanoyl)thiophen-2-yl]butan-1-ol,

[0303] 1-1330:2-amino-2-methyl-4-[5-(4-phenylbutanoyl)thiophen-2-yl]butan-1-ol,

[0304] 1-1331:2-amino-2-methyl-4-[5-(5-cyclohexylpentanoyl)thiophen-2-yl]butan-1-ol,

[0305] 1-1344:2-amino-2-methyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-ol,

[0306] 1-1357:2-amino-2-methyl-4-[5-(6-cyclohexylhexanoyl)thiophen-2-yl]butan-1-ol,

[0307] 1-1370:2-amino-2-methyl-4-[5-(6-phenylhexanoyl)thiophen-2-yl]butan-1-ol,

[0308] 1-1387:2-amino-2-methyl-4-[5-(3-cyclohexyloxypropanoyl)thiophen-2-yl]butan-1-ol,

[0309] 1-1400:2-amino-2-methyl-4-[5-(3-phenoxypropanoyl)thiophen-2-yl]butan-1-ol,

[0310] 1-1414:2-amino-2-methyl-4-[5-(4-cyclohexyloxybutanoyl)thiophen-2-yl]butan-1-ol,

[0311] 1-1468:2-amino-2-methyl-4-[5-(4-phenoxybutanoyl)thiophen-2-yl]butan-1-ol,1-1523:2-amino-2-methyl-4-[5-(5-cyclohexyloxypentanoyl)thiophen-2-yl]butan-1-ol,

[0312] 1-1523:2-amino-2-methyl-4-[5-(5-cyclohexyloxypentanoyl)thiophen-2-yl]butan-1-ol,

[0313] 1-1524:2-amino-2-methyl-4-[5-(5-phenoxypentanoyl)thiophen-2-yl]butan-1-ol,

[0314] 1-1527:2-amino-2-methyl-4-[5-(3-cyclohexylmethoxypropanoyl)thiophen-2-yl]butan-1-ol,

[0315] 1-1729:2-amino-2-methyl-4-[5-(4-cyclohexylmethoxyphenyl)thiophen-2-yl]butan-1-ol,

[0316] 1-1742:2-amino-2-methyl-4-[5-(4-cyclohexylethoxyphenyl)thiophen-2-yl]butan-1-ol,

[0317] 1-1744:2-amino-2-methyl-4-[5-(4-benzyloxyphenyl)thiophen-2-yl]butan-1-ol,

[0318] 1-1761:2-amino-2-ethyl-4-[5-(4-cyclohexylbutyl)thiophen-2-yl]butan-1-ol,

[0319] 1-1764:2-amino-2-ethyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol,

[0320] 1-1816:2-amino-2-ethyl-4-[5-(6-cyclohexylhexyl)thiophen-2-yl]butan-1-ol,

[0321] 1-1900:2-amino-2-ethyl-4-[5-(4-cyclohexylbut-1-ynyl)thiophen-2-yl]butan-1-ol,

[0322] 1-1909:2-amino-2-ethyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol,

[0323] 1-1962:2-amino-2-ethyl-4-[5-(6-cyclohexylhex-1-ynyl)thiophen-2-yl]butan-1-ol,

[0324] 1-2089:2-amino-2-ethyl-4-[5-(4-cyclohexylbutanoyl)thiophen-2-yl]butan-1-ol,

[0325] 1-2097:2-amino-2-ethyl-4-[5-(5-cyclohexylpentanoyl)thiophen-2-yl]butan-1-ol,

[0326] 1-463:2-amino-2-methyl-4-{5-[4-(4-fluorophenoxy)butyl]thiophen-2-yl}butan-1-ol,

[0327] 1-479:2-amino-2-methyl-4-{5-[4-(4-methoxyphenoxy)butyl]thiophen-2-yl}butan-1-ol,

[0328] 1-594:2-amino-2-methyl-4-[5-(4-benzyloxybutyl)thiophen-2-yl]butan-1-ol,

[0329] 1-760:2-amino-2-methyl-4-{5-[4-(4-fluorophenyl)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0330] 1-761:2-amino-2-methyl-4-{5-[4-(4-methylphenyl)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0331] 1-762:2-amino-2-methyl-4-{5-[4-(4-ethylphenyl)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0332] 1-763:2-amino-2-methyl-4-{5-[4-(4-trifluoromethylphenyl)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0333] 1-764:2-amino-2-methyl-4-{5-[4-(4-methoxyphenyl)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0334] 1-765:2-amino-2-methyl-4-{5-[4-(4-ethoxyphenyl)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0335] 1-766:2-amino-2-methyl-4-{5-[4-(4-methylthiophenyl)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0336] 1-832:2-amino-2-methyl-4-{5-[5-(3-fluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0337] 1-833:2-amino-2-methyl-4-{5-[5-(4-fluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0338] 1-834:2-amino-2-methyl-4-{5-[5-(4-chlorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0339] 1-836:2-amino-2-methyl-4-{5-[5-(3-methylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0340] 1-837:2-amino-2-methyl-4-{5-[5-(4-methylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0341] 1-846:2-amino-2-methyl-4-{5-[5-(3-trifluoromethylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0342] 1-847:2-amino-2-methyl-4-{5-[5-(4-trifluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0343] 1-848:2-amino-2-methyl-4-{5-[5-(3-methoxyphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0344] 1-849:2-amino-2-methyl-4-{5-[5-(4-methoxyphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0345] 1-860:2-amino-2-methyl-4-{5-[5-(3-methylthiophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0346] 1-861:2-amino-2-methyl-4-{5-[5-(4-methylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0347] 1-877:2-amino-2-methyl-4-{5-[5-(3,4-dimethylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0348] 1-878:2-amino-2-methyl-4-{5-[5-(3,5-dimethylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0349] 1-1050:2-amino-2-methyl-4-{5-[3-(4-methylcyclohexyloxy)propynyl]thiophen-2-yl}butan-1-ol,

[0350] 1-1062:2-amino-2-methyl-4-{5-[3-(4-fluorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0351] 1-1063:2-amino-2-methyl-4-{5-[3-(4-methylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0352] 1-1064:2-amino-2-methyl-4-{5-[3-(4-ethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0353] 1-1065:2-amino-2-methyl-4-{5-[3-(4-trifluoromethylphenyl)propynyl]thiophen-2-yl}butan-1-ol,

[0354] 1-1066:2-amino-2-methyl-4-{5-[3-(4-methoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0355] 1-1067:2-amino-2-methyl-4-{5-[3-(4-methoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0356] 1-1068:2-amino-2-methyl-4-{5-[3-(4-methylthiophenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0357] 1-1134:2-amino-2-methyl-4-{5-[4-(3-fluorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0358] 1-1135:2-amino-2-methyl-4-{5-[4-(4-fluorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0359] 1-1136:2-amino-2-methyl-4-{5-[4-(4-chlorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0360] 1-1138:2-amino-2-methyl-4-{5-[4-(3-methylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0361] 1-1139:2-amino-2-methyl-4-{5-[4-(4-methylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0362] 1-1148:2-amino-2-methyl-4-{5-[4-(3-trifluoromethylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0363] 1-1149:2-amino-2-methyl-4-{5-[4-(4-trifluoromethylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0364] 1-1150:2-amino-2-methyl-4-{5-[4-(3-methoxyphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0365] 1-1151:2-amino-2-methyl-4-{5-[4-(4-methoxyphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0366] 1-1162:2-amino-2-methyl-4-{5-[4-(3-methylthiophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0367] 1-1163:2-amino-2-methyl-4-{5-[4-(4-methylthiophenoxy)but-1-ynyl)thiophen-2-yl}butan-1-ol,

[0368] 1-1179:2-amino-2-methyl-4-{5-[4-(3,4-dimethylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0369] 1-1180: 2-amino-2-methyl-4-{5-[4-(3,4-dimethylphenoxy)but- I-ynyl]thiophen-2-yl}butan-1-ol,

[0370] 1-1198:2-amino-2-methyl-4-[5-(3-phenylmethoxypropynyl)thiophen-2-yl]butan-1-ol,

[0371] 1-1202:2-amino-2-methyl-4-{5-[3-(4-fluorophenyl)methoxypropynyl]thiophen-2-yl}butan-1-ol,

[0372] 1-1203:2-amino-2-methyl-4-{5-[3-(4-methylphenyl)methoxypropynyl]thiophen-2-yl}butan-1-ol,

[0373] 1-1204:2-amino-2-methyl-4-{5-[3-(4-ethylphenyl)methoxypropynyl]thiophen-2-yl}butan-1-ol,

[0374] 1-1205:2-amino-2-methyl-4-{5-[3-(4-trifluoromethylphenyl)methoxypropynyl]-thiophen-2-yl}butan-1-ol,

[0375] 1-1206:2-amino-2-methyl-4-{5-[3-(4-methoxyphenyl)methoxyproynyl]thiophen-2-yl}butan-1-ol,

[0376] 1-1207:2-amino-2-methyl-4-{5-[3-(4-ethoxyphenyl)methoxypropynyl]thiophen-2-yl}butan-1-ol,

[0377] 1-1208:2-amino-2-methyl-4-{5-[3-(4-methylthiophenyl)methoxypropynyl]-thiophen-2-yl}butan-1-ol,

[0378] 1-1212:2-amino-2-methyl-4-[5-(4-cyclohexylmethoxybut-1-ynyl)thiophen-2-yl]butan-1-ol,

[0379] 1-1266:2-amino-2-methyl-4-[5-(4-phenylmethoxybut-1-ynyl)thiophen-2-yl]butan-1-ol,

[0380] 1-1274:2-amino-2-methyl-4-{5-[4-(3-fluorophenyl)methoxybut-1-ynyl)thiophen-2-yl)butan-1-ol,

[0381] 1-1275:2-amino-2-methyl-4-{5-[4-(4-fluorophenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1-ol,

[0382] 1-1276:2-amino-2-methyl-4-{5-[4-(4-chlorophenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1-ol,

[0383] 1-1278:2-amino-2-methyl-4-{5-[4-(3-methylphenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1-ol,

[0384] 1-1279:2-amino-2-methyl-4-{5-[4-(4-methylphenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1-ol,

[0385] 1-1288:2-amino-2-methyl-4-{5-[4-(3-trifluoromethylphenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1-ol,

[0386] 1-1289:2-amino-2-methyl-4-{5-[4-(4-trifluoromethylphenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1-ol,

[0387] 1-1290:2-amino-2-methyl-4-{5-[4-(3-methoxyphenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1-ol,

[0388] 1-1291:2-amino-2-methyl-4-{5-[4-(4-methoxyphenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1-ol,

[0389] 1-1319:2-amino-2-methyl-4-{5-[4-(3,4-dimethylphenyl)methoxybut-1-ynyl]thiophen-2-yl)butan-1-ol,

[0390] 1-1320:2-amino-2-methyl-4-{5-[4-(3,5-dimethylphenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1-ol,

[0391] 1-1348:2-amino-2-methyl-4-{5-[5-(4-fluorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

[0392] 1-1349:2-amino-2-methyl-4-{5-[5-(4-methylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

[0393] 1-1350:2-amino-2-methyl-4-{5-[5-(4-ethylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

[0394] 1-1351:2-amino-2-methyl-4-{5-[5-(4-trifluoromethylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

[0395] 1-1352:2-amino-2-methyl-4-{5-[5-(4-methoxyphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

[0396] 1-1353:2-amino-2-methyl-4-{5-[5-(4-ethoxyphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

[0397] 1-1354:2-amino-2-methyl-4-{5-[5-(4-methylthiophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

[0398] 1-1476:2-amino-2-methyl-4-{5-[4-(3-fluorophenoxy)butanoyl]thiophen-2-yl}butan-1-ol,

[0399] 1-1477:2-amino-2-methyl-4-{5-[4-(4-fluorophenoxy)butanoyl]thiophen-2-yl}butan-1-ol,

[0400] 1-1478:2-amino-2-methyl-4-{5-[4-(4-chlorophenoxy)butanoyl]thiophen-2-yl}butan-1-ol,

[0401] 1-1480:2-amino-2-methyl-4-{5-[4-(3-methylphenoxy)butanoyl]thiophen-2-yl}butan-1-ol,

[0402] 1-1481:2-amino-2-methyl-4-{5-[4-(4-methylphenoxy)butanoyl]thiophen-2-yl}butan-1-ol,

[0403] 1-1490:2-amino-2-methyl-4-{5-[4-(3-trifluoromethylphenoxy)butanoyl]thiophen-2-yl)butan-1-ol,

[0404] 1-1491:2-amino-2-methyl-4-{5-[4-(4-trifluoromethylphenoxy)butanoyl]thiophen-2-yl}butan-1-ol,

[0405] 1-1492:2-amino-2-methyl-4-{5-[4-(3-methoxyphenoxy)butanoyl]thiophen-2-yl}butan-1-ol,

[0406] 1-1493:2-amino-2-methyl-4-{5-[4-(4-methoxyphenoxy)butanoyl]thiophen-2-yl}butan-1-ol,

[0407] 1-1504:2-amino-2-methyl-4-{5-[4-(3-methylthiophenyl)butanoyl]thiophen-2-yl}butan-1-ol,

[0408] 1-1505:2-amino-2-methyl-4-{5-[4-(4-methylthiophenoxy)butanoyl]thiophen-2-yl}butan-1-ol,

[0409] 1-1521:2-amino-2-methyl-4-{5-[4-(3,4-dimethylphenoxy)butanoyl]thiophen-2-yl}butan-1-ol,

[0410] 1-1522:2-amino-2-methyl-4-{5-[4-(3,5-dimethylphenoxy)butanoyl]thiophen-2-yl}butan-1-ol,

[0411] 1-2093:2-amino-2-ethyl-4-[5-(4-phenylbutanoyl)thiophen-2-yl]butan-1-ol,

[0412] 1-2101:2-amino-2-ethyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-ol,

[0413] 1-2109:2-amino-2-ethyl-4-[5-(4-phenylhexanoyl)thiophen-2-yl]butan-1-ol,

[0414] 1-2257:2-amino-2-methyl-4-{5-[5-(3,4-difluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0415] 1-2258:2-amino-2-methyl-4-{5-[5-(3,4-difluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0416] 1-2259:2-amino-2-methyl-4-{5-[5-(3-chlorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0417] 1-2260:2-amino-2-methyl-4-{5-[5-(3,4-dichlorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0418] 1-2261:2-amino-2-methyl-4-{5-[5-(3,4-dichlorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0419] 1-2262:2-amino-2-methyl-4-{5-[5-(3,4-ditrifluoromethylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0420] 1-2263:2-amino-2-methyl-4-{5-[5-(3,5-ditrifluoromethylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0421] 1-2264:2-amino-2-methyl-4-{5-[5-(3,4-dimethoxyphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0422] 1-2265:2-amino-2-methyl-4-{5-[5-(3,5-dimethoxyphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0423] 1-2266:2-amino-2-methyl-4-{5-[5-(3,4,5-trimethoxyphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0424] 1-2267:2-amino-2-methyl-4-{5-[5-(3-acetylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0425] 1-2268:2-amino-2-methyl-4-{5-[5-(4-acetylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0426] 1-2269:2-amino-2-methyl-4-{5-[3-(3-fluorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0427] 1-2270:2-amino-2-methyl-4-{5-[3-(3,4-difluorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0428] 1-2271:2-amino-2-methyl-4-{5-[3-(3,5-difluorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0429] 1-2272:2-amino-2-methyl-4-{5-[3-(3-chlorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0430] 1-2273:2-amino-2-methyl-4-{5-[3-(4-chlorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0431] 1-2274:2-amino-2-methyl-4-{5-[3-(3,⁴-dichlorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0432] 1-2275:2-amino-2-methyl-4-{5-[3-(3,5-dichlorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0433] 1-2276:2-amino-2-methyl-4-{5-[3-(3-methylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0434] 1-2278:2-amino-2-methyl-4-{5-[3-(3,4-dimethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0435] 1-2279:2-amino-2-methyl-4-{5-[3-(3,5-dimethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0436] 1-2280:2-amino-2-methyl-4-{5-[³-(3-trifluoromethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0437] 1-2281:2-amino-2-methyl-4-{5-[3-(3,4-difluoromethylphenoxy)propynyl]-thiophen-2-yl}butan-1-ol,

[0438] 1-2282:2-amino-2-methyl-4-{5-[3-(3,5-ditrifluoromethylphenoxy)propynyl]-thiophen-2-yl}butan-1-ol,

[0439] 1-2283:2-amino-2-methyl-4-{5-[3-(3-methoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0440] 1-2284:2-amino-2-methyl-4-{5-[3-(3,4-dimethoxyphenyl)propynyl]thiophen-2-yl}butan-1-ol,

[0441] 1-2285:2-amino-2-methyl-4-{5-[3-(3,5-dimethoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0442] 1-2286:2-amino-2-methyl-4-{5-[3-(3,4,5-trimethoxyphenoxy)propynylthiophen-2-yl)butan-1-ol,

[0443] 1-2287:2-amino-2-methyl-4-{5-[3-(3-acetylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0444] 1-2288:2-amino-2-methyl-4-{5-[3-(4-acetylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0445] 1-2290:2-amino-2-methyl-4-{5-[4-(3,4-difluorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0446] 1-2291:2-amino-2-methyl-4-{5-[4-(3,5-difluorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0447] 1-2292:2-amino-2-methyl-4-{5-[4-(3-chlorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0448] 1-2293:2-amino-2-methyl-4-{5-[4-(3,4-dichlorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0449] 1-2294:2-amino-2-methyl-4-{5-[4-(3,5-dichlorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0450] 1-2295:2-amino-2-methyl-4-{5-[4-(3,4-ditrifluoromethylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0451] 1-2296:2-amino-2-methyl-4-{5-[4-(3,5-ditrifluoromethylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0452] 1-2297:2-amino-2-methyl-4-{5-[4-(3,4-dimethoxyphenoxyl)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0453] 1-2298:2-amino-2-methyl-4-{5-[4-(3,5-dimethoxyphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0454] 1-2299:2-amino-2-methyl-4-{5-[4-(3,4,5-trimethoxyphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0455] 1-2300:2-amino-2-methyl-4-{5-[4-(3-acetylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0456] 1-2301:2-amino-2-methyl-4-{5-[4-(4-acetylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0457] 1-2328:2-amino-2-methyl-4-{5-[5-(3-fluorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

[0458] 1-2329:2-amino-2-methyl-4-{5-[5-(3,4-difluorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

[0459] 1-2330:2-amino-2-methyl-4-{5-[5-(3,5-difluorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

[0460] 1-2331:2-amino-2-methyl-4-{5-[5-(3-chlorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

[0461] 1-2332:2-amino-2-methyl-4-{5-[5-(4-chlorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

[0462] 1-2333:2-amino-2-methyl-4-{5-[5-(3,4-dichlorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

[0463] 1-2334:2-amino-2-methyl-4-{5-[5-(3,5-dichlorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

[0464] 1-2335:2-amino-2-methyl-4-{5-[5-(3-methylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

[0465] 1-2336:2-amino-2-methyl-4-{5-[5-(3,4-dimethylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

[0466] 1-2337:2-amino-2-methyl-4-{5-[5-(3,4-dimethylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

[0467] 1-2338:2-amino-2-methyl-4-{5-[5-(3-trifluoromethylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

[0468] 1-2339:2-amino-2-methyl-4-{5-[5-(3,⁴-ditrifluoromethylphenyl)pentanoyl]-thiophen-2-yl}butan-1-ol,

[0469] 1-2340:2-amino-2-methyl-4-{5-[5-(3,5-ditrifluoromethylphenyl)pentanoyl]-thiophen-2-yl}butan-1-ol,

[0470] 1-2341:2-amino-2-methyl-4-{5-[5-(3-methoxyphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

[0471] 1-2342:2-amino-2-methyl-4-{5-[5-(3,4-dimethoxyphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

[0472] 1-2343:2-amino-2-methyl-4-{5-[5-(3,5-dimethoxyphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

[0473] 1-2344:2-amino-2-methyl-4-{5-[5-(3,4,5-trimethoxyphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

[0474] 1-2345:2-amino-2-methyl-4-{5-[5-(3-acetylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,and

[0475] 1-2346:2-amino-2-methyl-4-{5-[5-(4-acetylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol.

[0476] Most preferred compounds are those of Exemplificaion compoundsnumbers:

[0477] 1-71:2-amino-2-methyl-4-[5-(4-cyclohexylbutyl)thiophen-2-yl]butan-1-ol,

[0478] 1-98:2-amino-2-methyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol,

[0479] 1-152:2-amino-2-methyl-4-[5-(5-phenylpentyl)thiophen-2-yl]butan-1-ol,

[0480] 1-400:2-amino-2-methyl-4-[5-(4-cyclohexyloxybutyl)thiophen-2-yl]butan-1-ol,

[0481] 1-463:2-amino-2-methyl-4-{5-[4-(4-fluorophenoxy)butyl]thiophen-2-yl}butan-1-ol,

[0482] 1-479:2-amino-2-methyl-4-{5-[4-(4-methoxyphenoxy)butyl]thiophen-2-yl}butan-1-ol,

[0483] 1-594:2-amino-2-methyl-4-[5-(4-benzyloxybutyl)thiophen-2-yl]butan-1-ol,

[0484] 1-743:2-amino-2-methyl-4-[5-(4-cyclohexylbut-1-ynyl)thiophen-2-yl]butan-1-ol,

[0485] 1-756:2-amino-2-methyl-4-[5-(4-phenylbut-1-ynyl)thiophen-2-yl]butan-1-ol,

[0486] 1-770:2-amino-2-methyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol,

[0487] 1-824:2-amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol,

[0488] 1-833:2-amino-2-methyl-4-{5-[5-(4-fluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0489] 1-849:2-amino-2-methyl-4-{5-[5-(4-methoxyphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

[0490] 1-1050:2-amino-2-methyl-4-{5-[3-(4-methylcyclohexyloxy)propynyl]thiophen-2-yl}butan-1-ol,

[0491] 1-1063:2-amino-2-methyl-4-{5-[3-(4-methylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0492] 1-1064:2-amino-2-methyl-4-{5-[3-(4-ethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0493] 1-1068:2-amino-2-methyl-4-{5-[3-(4-methylthiophenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0494] 1-1072:2-amino-2-methyl-4-[5-(4-cyclohexyloxybut-1-ynyl)thiophen-2-yl]butan-1-ol,

[0495] 1-1135:2-amino-2-methyl-4-{5-[4-(4-fluorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0496] 1-1139:2-amino-2-methyl-4-{5-[4-(4-methylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

[0497] 1-1185:2-amino-2-methyl-4-[5-(3-cyclohexylmethoxypropynyl)thiophen-2-yl]butan-1-ol,

[0498] 1-1266:2-amino-2-methyl-4-[5-(4-phenylmethoxybut-1-ynyl)thiophen-2-yl]butan-1-ol,

[0499] 1-1329:2-amino-2-methyl-4-[5-(4-cyclohexylbutanoyl)thiophen-2-yl]butan-1-ol,

[0500] 1-1330:2-amino-2-methyl-4-[5-(4-phenylbutanoyl)thiophen-2-yl]butan-1-ol,

[0501] 1-1331:2-amino-2-methyl-4-[5-(5-cyclohexylpentanoyl)thiophen-2-yl]butan-1-ol,

[0502] 1-1344:2-amino-2-methyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-ol,

[0503] 1-1348:2-amino-2-methyl-4-{5-[5-(4-fluorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

[0504] 1-1764:2-amino-2-ethyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol,

[0505] 1-1909:2-amino-2-ethyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol,

[0506] 1-2097:2-amino-2-ethyl-4-[5-(5-cyclohexylpentanoyl)thiophen-2-yl]butan-1-ol,

[0507] 1-2273:2-amino-2-methyl-4-{5-[3-(4-chlorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0508] 1-2276:2-amino-2-methyl-4-{5-[3-(3-methylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0509] 1-2278:2-amino-2-methyl-4-{5-[3-(3,4-dimethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0510] 1-2283:2-amino-2-methyl-4-{5-[3-(3-methoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0511] 1-2284:2-amino-2-methyl-4-{5-[3-(3,4-dimethoxyphenyl)propynyl]thiophen-2-yl}butan-1-ol,

[0512] 1-2285:2-amino-2-methyl-4-{5-[3-(3,5-dimethoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

[0513] 1-2287:2-amino-2-methyl-4-{5-[3-(3-acetylphenoxy)propynyl)thiophen-2-yl}butan-1-ol,and

[0514] 1-2288:2-amino-2-methyl-4-{5-[3-(4-acetylphenoxy)propynyl]thiophen-2-yl}butan-1-ol.TABLE 3 (La)

Exemp. Compd. No. R^(4a) R¹ R² R^(3a) Ar m 3-1 Me H Boc TBDMS Ph 0 3-2Me H Bz TBDMS Ph 0 3-3 Me H Ac TBDMS Ph 0 3-4 Me H Boc H 2-Fur 0 3-5 MeH Boc H 2-The 0 3-6 Me H Ac H 2-The 0 3-7 Me H Bz H 2-The 0 3-8 Me H BocH 6-Bzt 0 3-9 Et H Boc TBDMS Ph 0 3-10 Et H Ac H 2-Fur 0 3-11 Et H Boc H2-The 0 3-12 Et H Boc H 6-Bzt 0 3-13 Me H Ac Ac 2-The 0 3-14 Me H Ac Ac2-Fur 0 3-15 Me H Ac Ac 2-Bzt 0

[0515] TABLE 4 (La-1)

Exemp. Compd. No. R^(4a) Ar m 4-1 Me Ph 0 4-2 Me 2-Fur 0 4-3 Me 3-Fur 04-4 Me 2-The 0 4-5 Me 3-The 0 4-6 Me 4-Br-2-The 0 4-7 Me 4-Br-3-The 04-8 Me 5-Br-2-The 0 4-9 Me 5-Br-3-The 0 4-10 Me 4-Cl-2-The 0 4-11 Me4-Cl-3-The 0 4-12 Me 5-Cl-2-The 0 4-13 Me 5-Cl-3-The 0 4-14 Me 2-Pyr 04-15 Me 3-Pyr 0 4-16 Me 4-Pyr 0 4-17 Me 6-Bzt 0 4-18 Me Np(1) 0 4-19 MeNp(2) 0 4-20 Me 6-Bpyrr 0 4-21 Et Ph 0 4-22 Et 2-Fur 0 4-23 Et 2-The 04-24 Et 6-Bzt 0 4-25 Pr Ph 0 4-26 Pr 2-Fur 0 4-27 Et 2-The 0 4-28 Et6-Bzt 0 4-29 Bu Ph 0 4-30 Bu 2-Fur 0 4-31 Et 2-The 0 4-32 Et 6-Bzt 0

[0516] Preferred compounds in Table 3 and 4 are those of Exemplificationcompounds numbers 3-5, 3-6, 3-7, 3-8, 3-11, 3-12, 4-4, 4-5, 4-6, 4-7,4-8, 4-9, 4-10, 4-11, 4-12, 4-13, 4-17, 4-23, 4-24, 4-27, 4-28, 4-31,and 4-32.

[0517] Most preferred compounds are those Exemplification compoundsnumbers:

[0518] 4-4: 4-methyl-4-[(thiophen-3-yl)ethyl]oxazolidinone,

[0519] 4-5: 4-methyl-4-[(thiophen-3-yl)ethyl]oxazolidinone,

[0520] 4-8: 4-methyl-4-[(5-bromothiophen-3-yl)ethyl]oxazolidinone, and

[0521] 4-9: 4-methyl-4-[(5-bromothiophen-3-yl)ethyl]oxazolidinone.

[0522] Compounds of formulae (I), (XLIVa), (XLIVb), (La) and (Lb) can beprepared according to the methods described below.

[0523] In method A, a compound (I) and a compound (Ic) (which is acompound (I) where R¹ is a hydrogen atom and R² is a loweralkoxycarbonyl group, an aralkyloxycarbonyl group or anaralkyloxycarbonyl group substituted by 1-3 substituents selected fromthe substituent group a) are synthesized.

[0524] In the above scheme, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X, Y and n areas defined earlier; R⁸ is a formyl group, a carboxyl group or a loweralkoxycarbonyl group; R⁹ and R^(9a) are the same or different and eachis independently a hydrogen atom or a lower alkyl group; R¹⁰ is a loweralkyl group, an aralkyl group or an aralkyl group substituted by 1-3substituents selected from the substituent group a; and R^(5a), R^(6a)and R^(7a) are an amino group, a hydroxyl group and/or a carboxyl group,each of which is contained as the substituent in each definition of R⁵,R⁶ and R⁷ and optionally protected by a suitable protecting group, inaddition to the same groups as those defined earlier for R⁵, R⁶ and R⁷.

[0525] In the above description, the “protecting group” of the “aminogroup optionally protected” in the definition of R^(5a), R^(6a) andR^(7a) is not particularly limited provided that it is a protectinggroup of an amino group used in the field of the organic syntheticchemistry and is the same as that defined earlier. A loweralkoxycarbonyl group is preferred and a t-butoxycarbonyl group is mostpreferred.

[0526] In the above description, the “protecting group” of the “hydroxylgroup optionally protected” in the definition of R^(5a), R^(6a) andR^(7a) is not particularly limited provided that it is a protectinggroup of a hydroxyl group used in the field of the organic syntheticchemistry. This protecting group is, for example, the same as thatdefined earlier as the “common protecting group used for the protectionof a hydroxyl group by esterification”, and the preferable examplesinclude a lower aliphatic acyl group, an aromatic acyl group, a loweralkoxycarbonyl group or a (lower alkoxy)methyl group, and morepreferable examples are a lower aliphatic acyl group or a (loweralkoxycarbonyl)methyl group. The most preferable example is an acetylgroup or a methoxymethyl group.

[0527] In the above description, the “protecting group” of the “carboxylgroup optionally protected” in the definition of R^(5a), R^(6a) andR^(7a) is not particularly limited provided that it is a protectinggroup of a carboxyl group used in the field of the organic syntheticchemistry. This protecting group is, for example, the same as thatdefined earlier as the “common protecting groups used for the protectionof a carboxyl group by esterification”, and the preferable examplesinclude a lower alkyl group, and a methyl group is most preferable.

[0528] In Step A1, a compound of general formula (III) is prepared bythe reaction of a compound of general formula (II) with a reducing agentin an inert solvent in the presence or absence of a base (preferably inthe presence of a base).

[0529] The inert solvent used in the above-mentioned reaction is notparticularly limited provided that it has no adverse effect on thereaction and dissolves the starting materials to some extent. Examplesof suitable solvents include aliphatic hydrocarbons such as hexane,heptane, ligroin or petroleum ether; aromatic hydrocarbons such asbenzene, toluene or xylene; halogenated hydrocarbons such as chloroform,methylene chloride, 1,2-dichloroethane or carbon tetrachloride; esterssuch as acetic acid, methyl acetate, ethyl acetate, propyl acetate,butyl acetate or diethyl carbonate; ethers such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordi(ethylene glycol) dimethyl ether; alcohols such as methanol, ethanol,n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamylalcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methylcellosolve; amides such as formamide, dimethylformamide,dimethylacetamide or hexamethylphosphoric triamide; water; or mixturesof water and solvents thereof or of solvents thereof. Of these solvents,ethers are preferred and tetrahydrofuran is most preferred.

[0530] The reducing agent used in the above-mentioned reaction is, forexample, an alkali metal borohydride such as sodium borohydride, lithiumborohydride or sodium cyanoborohydride; or an aluminium hydridederivative such as diisobutylaluminium hydride, lithium aluminiumhydride or triethoxyaluminium lithium hydride. The preferred examplesare alkali metal borohydrides, and sodium borohydride is most preferred.

[0531] The reaction temperature mainly depends on the starting materialcompounds, the reducing agent and the solvent employed in the reaction.The reaction is usually carried out at a temperature of from −50° C. to100° C. (preferably from 0° C. to 50° C.).

[0532] The reaction time mainly depends on the starting materialcompounds, the reducing agent, the solvent and the reaction temperatureemployed in the reaction. The reaction is usually carried out in aperiod of from 15 minutes to 150 hours (preferably from 1 hour to 100hours). After the completion of the reaction, the target compounds (III)of this reaction may be collected from the reaction mixture according toconventional methods. For example, the target compound can be obtainedby conducting the following steps successively: appropriatelyneutralizing the reaction mixture; removing, if any, insolublematerial(s) by filtration; adding an organic solvent which is notmiscible with water (e.g. ethyl acetate); separating the organic layercontaining the target compound; washing the extract with, for example,water and then drying over anhydrous magnesium sulfate, anhydrous sodiumsulfate, anhydrous sodium bicarbonate or the like; and removing solventby evaporation. The target compound can be isolated and purified, ifnecessary, by a suitable combination of the conventional methodscommonly used for the separation/purification of organic compounds suchas recrystallization, reprecipitation and chromatography usingappropriate eluent(s).

[0533] In Step A2, a compound of general formula (IV) is prepared byconverting a hydroxyl group in the compound of formula (III) into aleaving group in an inert solvent in the presence of a base and then byiodination reaction of the resulting leaving group with an iodinationagent. The reagent used for the formation of the leaving group is, forexample, a halogenation agent including sulfonyl halides such asmethanesulfonyl chloride or p-toluenesulfonyl chloride; thionyl halidessuch as thionyl chloride, thionyl bromide or thionyl iodide; sulfurylhalides such as sulfuryl chloride, sulfuryl bromide or sulfuryl iodide;phosphorus trihalogenides such as phosphorus trichloride, phosphorustribromide or phosphorus triiodide; phosphorus pentahalogenides such asphosphorus pentachloride, phosphorus pentabromide or phosphoruspentaiodide; phosphorus oxyhalogenides such as phosphorus oxychloride,phosphorus oxybromide or phosphorus oxyiodide; or rhenium reagents suchas methyltrioxorhenium (VII). Of these reagents, sulfonyl halides arepreferred.

[0534] Examples of bases which can be used in the conversion of thehydroxyl group into the leaving group include alkali metal carbonatessuch as lithium carbonate, sodium carbonate or potassium carbonate;alkali metal bicarbonates such as lithium bicarbonate, sodiumbicarbonate or potassium bicarbonate; alkali metal hydrides such aslithium hydride, sodium hydride or potassium hydride; alkali metalhydroxides such as lithium hydroxide, sodium hydroxide or potassiumhydroxide; alkali metal alkoxides such as lithium methoxide, sodiummethoxide, sodium ethoxide or potassium t-butoxide; and organic aminessuch as triethylamine, tributylamine, diisopropylethylamine,N-methylmorpholine, pyridirie, 4-(N,N-dimethylamino)pyridine,N,N-dimethylaniline, N,N-diethylaniline,1,5-diazabicyclo[4.3.0]nona-5-ene, 1,4-diazabicyclo[2.2.2]-octane(DABCO) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The organic amines(particularly triethylamine) are preferable.

[0535] The inert solvent which can be used in the conversion of thehydroxyl group into the leaving group is not particularly limitedprovided that it has no adverse effect on the reaction. Examples ofsuitable solvents include aliphatic hydrocarbons such as hexane,heptane, ligroin or petroleum ether; aromatic hydrocarbons such asbenzene, toluene or xylene; halogenated hydrocarbons such as chloroform,methylene chloride, 1,2-dichloroethane or carbon tetrachloride; etherssuch as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane or di(ethylene glycol) dimethyl ether; ketones such asacetone or 2-butanone; amides such as formamide, dimethylformamide,dimethylacetamide or hexamethylphosphoric triamide; sulfoxides such asdimethyl sulfoxide; or sulfolane. Of these solvents, halogenatedhydrocarbons are preferred and methylene chloride is most preferred.

[0536] The reaction temperature-in the case of the conversion of thehydroxyl group into the leaving group mainly depends on the startingmaterial compounds, the reagent and the solvent employed in thereaction. The reaction is usually carried out at a temperature of from−50° C. to 200° C. (preferably from −10° C. to 150° C.).

[0537] The reaction time in the case of the conversion of the hydroxylgroup into the leaving group mainly depends on the starting materialcompounds, the reagent, the solvent and the reaction temperatureemployed in the reaction. The reaction is usually carried out in aperiod of from 15 minutes to 24 hours (preferably from 30 minutes to 12hours).

[0538] The iodination agent that can be used in the above-mentionedreaction is, for example, phosphorus pentaiodide, phosphorus oxyiodide,sodium iodide or potassium iodide, and sodium iodide is preferred.

[0539] The reaction temperature in the case of the iodination of theleaving group mainly depends on the starting material compounds, thereagent and the solvent employed in the reaction. The reaction isusually carried out at a temperature of from 0° C. to 200° C.(preferably from 10° C. to 150° C.).

[0540] The reaction time in the case of the iodination of the leavinggroup mainly depends on the starting material compounds, the reagent,the solvent and the reaction temperature employed in the reaction. Thereaction is usually carried out in a period of from 15 minutes to 24 hrs(preferably from 30 minutes to 12 hours).

[0541] After the completion of the reaction, the target compounds (IV)of this reaction may be collected from the reaction mixture according toconventional methods. For example, the target compound can be obtainedby conducting the following steps successively: appropriatelyneutralizing the reaction mixture; removing, if any, insolublematerial(s) by filtration; adding an organic solvent which is notmiscible with water (e.g. ethyl acetate); separating the organic layercontaining the target compound; washing the extract with, for example,water and then drying over anhydrous magnesium sulfate, anhydrous sodiumsulfate, anhydrous sodium bicarbonate or the like; and removing solventby evaporation. The target compound can be isolated and purified, ifnecessary, by a suitable combination of the conventional methodscommonly used for the separation/purification of organic compounds suchas recrystallization, reprecipitation and chromatography usingappropriate eluent(s).

[0542] In Step A3, a compound of general formula (VI) is prepared by thereaction of a compound (IV) with a compound of general formula (V) in aninert solvent in the presence of a base.

[0543] The inert solvent used in the above-mentioned reaction is notparticularly limited provided that it has no adverse effect on thereaction. Examples of suitable solvents include ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordi(ethylene glycol) dimethyl ether; alcohols such as methanol, ethanol,n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamylalcohol, diethylene glycol, glycerol, octanol, glycol) dimethyl ether;alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol,isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerol,octanol, solvents thereof or of solvents thereof. Of these solvents,alcohols or amides are preferred and dimethylformamide is mostpreferred.

[0544] The base used in the above-mentioned reaction is, for example,the same as that used for the conversion of the hydroxyl group into theleaving group described in Step A2 of the method A, and alkali metalhydrides or alkali metal alkoxides (most preferably sodium hydride) arepreferred.

[0545] The reaction temperature mainly depends on the starting materialcompounds, the base and the solvent employed in the reaction. Thereaction is usually carried out at a temperature of from −78° C. to 100°C. (preferably from 0° C. to 50° C.).

[0546] The reaction time mainly depends on the starting materialcompounds, the base, the solvent and the reaction temperature employedin the reaction. The reaction is usually carried out in a period of from15 minutes to 48 hours (preferably from 30 minutes to 12 hours). Afterthe completion of the reaction, the target compounds (VI) of thisreaction may be collected from the reaction mixture according toconventional methods. For example, the target compound can be obtainedby conducting the following steps successively: appropriatelyneutralizing the reaction mixture; removing, if any, insolublematerial(s) by filtration; adding an organic solvent which is notmiscible with water (e.g. ethyl acetate); separating the organic layercontaining the target compound; washing the extract with, for example,water and then drying over anhydrous magnesium sulfate, anhydrous sodiumsulfate, anhydrous sodium bicarbonate or the like; and removing solventby evaporation. The target compound can be isolated and purified, ifnecessary, by a suitable combination of the conventional methodscommonly used for the separation/purification of organic compounds suchas recrystallization, reprecipitation and chromatography usingappropriate eluent(s).

[0547] In Step A4, a compound of general formula (VII) is prepared byconverting an ester group of a compound (VI) into a carboxyl group by ahydrolysis reaction with a base.

[0548] The inert solvent used in the above-mentioned reaction is notparticularly limited provided that it has no adverse effect on thereaction. Examples of suitable solvents include aliphatic hydrocarbonssuch as hexane, heptane, ligroin or petroleum ether; aromatichydrocarbons such as benzene, toluene or xylene; ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordi(ethylene glycol) dimethyl ether; alcohols such as methanol, ethanol,n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamylalcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methylcellosolve; water; or mixtures of water and solvents thereof or ofsolvents thereof. Of these solvents, alcohols (particularly ethanol) arepreferred.

[0549] The base used in the above-mentioned reaction is, for example,the same as that used for the conversion of a hydroxyl group into aleaving group described in Step A2 of the method A, and alkali metalhydroxides (most preferably potassium hydroxide) are preferred.

[0550] The reaction temperature mainly depends on the starting materialcompounds, the base and the solvent employed in the reaction. Thereaction is usually carried out at a temperature of from −20° C. to 200°C. (preferably from 0° C. to 50° C.).

[0551] The reaction time mainly depends on the starting materialcompounds, the base, the solvent and the reaction temperature employedin the reaction. The reaction is usually carried out in a period of from30 minutes to 120 hours (preferably from 1 hour to 80 hours). After thecompletion of the reaction, the compound (VII) prepared as the targetcompound in this reaction may be collected from the reaction mixtureaccording to a conventional method. For example, the target compound canbe obtained by conducting the following steps successively:appropriately neutralizing the reaction mixture; removing, if any,insoluble material(s) by filtration; adding an organic solvent which isnot miscible with water (e.g. ethyl acetate); separating the organiclayer containing the target compound; washing the extract with, forexample, water and then drying over anhydrous magnesium sulfate,anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; andremoving solvent by evaporation. The target compound can be isolated andpurified, if necessary, by a suitable combination of the conventionalmethods commonly used for the separation/purification of organiccompounds such as recrystallization, reprecipitation and chromatographyusing appropriate eluent(s).

[0552] Step A5 is a step for converting a carboxyl group into acarbamoyl group by the Curtius Rearrangement Reaction, and in this step,a compound of general formula (IX) is synthesized by the reaction of acompound (VII) with a diarylphosphoryl azide derivative such asdiphenylphosphoryl azide in an inert solvent in the presence of a baseand then by heating the resulting product with a compound of generalformula (VIII).

[0553] The inert solvent used in the above-mentioned reaction is notparticularly limited provided that it has no adverse effect on thereaction. Examples of suitable solvents include aliphatic hydrocarbonssuch as hexane, heptane, ligroin or petroleum ether; aromatichydrocarbons such as benzene, toluene or xylene; halogenatedhydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethaneor carbon tetrachloride; ethers such as diethyl ether, diisopropylether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; water; or mixtures of water and solvents thereof or ofsolvents thereof. Of these solvents, aromatic hydrocarbons (particularlybenzene) are preferred.

[0554] The base used in the above-mentioned reaction is, for example,the same as that used for the conversion of a hydroxyl group into aleaving group described in Step A2 of the method A, and organic amines(most preferably triethylamine) are preferred.

[0555] The reaction temperature for the reactions of the compound (VII)with diarylphophoryl azide derivative and of the resulting product withthe compound (VIII) mainly depends on the starting material compounds,the base and the solvent employed in the reaction. The reaction isusually carried out at a temperature of from 0° C. to 200° C.(preferably from 20° C. to 150° C.).

[0556] The reaction time for the reactions of the compound (VII) withdiarylphophoryl azide derivative and of the resulting product with thecompound (VIII) mainly depends on the starting material compounds, thebase, the solvent and the reaction temperature employed in the reaction.The reaction is usually carried out in the period of from 15 minutes to24 hours (preferably from 30 minutes to 12 hours).

[0557] In addition, even in the case where a compound (VIII) which isdifficult to react directly with a diarylphophoryl azide derivative isused, the carboxyl group of the compound (VII) can be converted into thecarbamoyl group without any problem by the reaction mentioned above.After the completion of the reaction, the compound (IX) prepared as thetarget compound in this reaction may be collected from the reactionmixture according to a conventional method. For example, the targetcompound can be obtained by conducting the following steps successively:appropriately neutralizing the reaction mixture; removing, if any,insoluble material(s) by filtration; adding an organic solvent which isnot miscible with water (e.g. ethyl acetate); separating the organiclayer containing the target compound; washing the extract with, forexample, water and then drying over anhydrous magnesium sulfate,anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; andremoving solvent by evaporation. The target compound can be isolated andpurified, if necessary, by a suitable combination of the conventionalmethods commonly used for the separation/purification of organiccompounds such as recrystallization, reprecipitation and chromatographyusing appropriate eluent(s).

[0558] In Step A6, a compound of general formula (X) is prepared byreducing an ester group of a compound (IX) with a reducing agent in aninert solvent.

[0559] The inert solvent used in the above-mentioned reaction is notparticularly limited provided that it has no adverse effect on thereaction. Examples of suitable solvents include aliphatic hydrocarbonssuch as hexane, heptane, ligroin or petroleum ether; aromatichydrocarbons such as benzene, toluene or xylene; halogenatedhydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethaneor carbon tetrachloride; ethers such as diethyl ether, diisopropylether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; alcohols such as methanol, ethanol, n-propanol,isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve;or mixtures of solvents thereof. Of these solvents, mixtures of alcoholsand ethers (particularly a mixture of ethanol and tetrahydrofuran) arepreferred.

[0560] The reducing agent used in the above-mentioned reaction is, forexample, the same as that used in Step A1 of the method A, and alkalimetal borohydrides (most preferably sodium borohydride or lithiumborohydride) are preferred.

[0561] The reaction temperature mainly depends on the starting materialcompounds and the solvent employed in the reaction. The reaction isusually carried out at a temperature of from −78° C. to 150° C.(preferably from −20° C. to 50° C.).

[0562] The reaction time mainly depends on the starting materialcompounds, the solvent and the reaction temperature employed in thereaction. The reaction is usually carried out in a period of from 5minutes to 48 hours (preferably from 30 minutes to 24 hours).

[0563] After the completion of the reaction, the compound (X) preparedas the target compound in this reaction may be collected from thereaction mixture according to a conventional method. For example, thetarget compound can be obtained by conducting following the stepssuccessively: appropriately neutralizing the reaction mixture; removing,if any, insoluble material(s) by filtration; adding an organic solventwhich is not miscible with water (e.g. ethyl acetate); separating theorganic layer containing the target compound; washing the extract with,for example, water and then drying over anhydrous magnesium sulfate,anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; andremoving solvent by evaporation. The target compound can be isolated andpurified, if necessary, by a suitable combination of the conventionalmethods commonly used for the separation/purification of organiccompounds such as recrystallization, reprecipitation and chromatographyusing appropriate eluent(s).

[0564] In Step A7, a compound of general formula (XI) having anoxazolidine ring is prepared by the reaction of a compound (X) with abase.

[0565] The inert solvent used in the above-mentioned reaction is notparticularly limited provided that it has no adverse effect on thereaction. Examples of suitable solvents include ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordi(ethylene glycol) dimethyl ether; alcohols such as methanol, ethanol,n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamylalcohol, diethylene glycol, glycerol, octanol, glycol) dimethyl ether;alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol,isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerol,octanol, solvents thereof or of solvents thereof. Of these solvents,alcohols or amides (particularly dimethylformamide) are preferred.

[0566] The base used in the above-mentioned reaction is, for example,the same as that used for the conversion of the hydroxyl group into theleaving group described in Step A2 of the method A, and alkali metalalkoxides (most preferably potassium t-butoxide) are preferred.

[0567] The reaction temperature mainly depends on the starting materialcompounds, the base and the solvent employed in the reaction. Thereaction is usually carried out at a temperature of from −78° C. to 100°C. (preferably from −50° C. to 50° C.).

[0568] The reaction time mainly depends on the starting materialcompounds, the base, the solvent and the reaction temperature employedin the reaction. The reaction is usually carried out in a period of from15 minutes to 48 hours (preferably from 30 minutes to 12 hours).

[0569] After the completion of the reaction, the compound (XI) preparedas the target compound in this reaction may be collected from thereaction mixture according to a conventional method. For example, thetarget compound can be obtained by conducting the following stepssuccessively: appropriately neutralizing the reaction mixture; removing,if any, insoluble material(s) by filtration; adding an organic solventwhich is not miscible with water (e.g. ethyl acetate); separating theorganic layer containing the target compound; washing the extract with,for example, water and then drying over anhydrous magnesium sulfate,anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; andremoving solvent by evaporation. The target compound can be isolated andpurified, if necessary, by a suitable combination of conventionalmethods commonly used for the separation/purification of organiccompounds such as recrystallization, reprecipitation and chromatographyusing appropriate eluent(s).

[0570] In Step A8, a compound of general formula (I) is prepared byhydrolyzing a compound (XI) with a base in an inert solvent and then, ifnecessary, by conducting successively the removal of an amino-, ahydroxyl- and/or a carboxyl-protecting group in R¹, R², R³, R^(5a),R^(6a) and R^(7a), and the protection of an amino group in R¹ and/or R²,and/or a protection of a hydroxyl group in R³.

[0571] The inert solvent used in the reaction of the compound (XI) withthe base is not particularly limited provided that it has no adverseeffect on the reaction. Examples of suitable solvents include aliphatichydrocarbons such as hexane, heptane, ligroin or petroleum ether;aromatic hydrocarbons such as benzene, toluene or xylene; halogenatedhydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethaneor carbon tetrachloride; ethers such as diethyl ether, diisopropylether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; alcohols such as methanol, ethanol, n-propanol,isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, glycol) dimethyl ether; alcoholssuch as methanol, ethanol, n-propanol, isopropanol, n-butanol,isobutanol, t-butanol, isoamyl alcohol, di ethylene glycol, glycerol,octanol, preferred.

[0572] The base used in the reaction of the compound (XI) with the baseis, for example, the same as that used for the conversion of a hydroxylgroup into a leaving group described in Step A2 of the method A, andalkali metal hydroxides (most preferably potassium hydroxide) arepreferred.

[0573] The reaction temperature mainly depends on the starting materialcompounds, the base and the solvent employed in the reaction. Thereaction is usually carried out at a temperature of from −20° C. to 200°C. (preferably from 0° C. to 100° C.).

[0574] The reaction time mainly depends on the starting materialcompounds, the base, the solvent and the reaction temperature employedin the reaction. The reaction is usually carried out in a period of from30 minutes to 48 hours (preferably from 1 hour to 24 hours).

[0575] The procedures for removing the amino- and thehydroxyl-protecting groups depend on the nature of the protecting groupused, but the removal of the protecting group is generally carried outaccording to the known procedures commonly used in organic syntheticchemistry. This deprotection reaction is, for example, performed by theprocedures described in the literature (T. W. Green: Protective Groupsin Organic Synthesis, John Wiley & Sons, and J. F. W. McOmis: ProtectiveGroups in Organic Chemistry, Plenum Press) as described below.

[0576] Where the amino-protecting group is a silyl group, thedeprotection reaction is usually carried out by treating with a compoundfrom which a fluorine anion is generated, such as tetrabutylammoniumfluoride, hydrofluoric acid, hydrofluoric acid-pyridine or potassiumfluoride.

[0577] The solvent used in the above-mentioned reaction is notparticularly limited provided that it has no adverse effect on thereaction. Examples of preferable solvents include ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordi(ethylene glycol) dimethyl ether.

[0578] The reaction temperature and reaction time are not particularlylimited. The deprotection reaction is usually carried out at atemperature of from 0° C. to 50° C. in a period of from 10 minutes to 18hours.

[0579] Where the amino-protecting group is either an aliphatic acylgroup, an aromatic acyl group, reaction is usually carried out at atemperature of from 0C to 50° C. in a period of from 10 reaction isusually carried out at a temperature of from 0C to 50° C. in a period offrom 10 aqueous solvent.

[0580] The acid used in the above-mentioned reaction is not particularlylimited provided that it is usually used as an acid and has no adverseeffect on the reaction. Examples of suitable acids include inorganicacids such as hydrobromic acid, hydrochloric acid, sulfuric acid,perchloric acid or phosphoric acid, and hydrochloric acid is preferable.

[0581] The base that can be used in the above-described reaction is notparticularly limited provided that it has no adverse effect on thestructural moieties other than the protecting group. Examples ofpreferred bases include alkali metal carbonates such as lithiumcarbonate, sodium carbonate or potassium carbonate; alkali metalhydroxides such as lithium hydroxide, sodium hydroxide or potassiumhydroxide; alkali metal alkoxides such as lithium methoxide, sodiummethoxide, sodium ethoxide or potassium t-butoxide; or ammonia solutionssuch as ammonia solution or concentrated methanolic ammonia solution.

[0582] The solvent used in the above-mentioned reaction is notparticularly limited provided that it is usually used in hydrolysisreactions. Examples of suitable solvents include alcohols such asmethanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol,t-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol,cyclohexanol or methyl cellosolve; ethers such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordi(ethylene glycol) dimethyl ether; water; or mixtures of water and oneor more organic solvents thereof. Ethers (particularly dioxane) arepreferable.

[0583] The reaction temperature and reaction time mainly depend on thestarting material compounds, the solvent and the acid or base employedin the reaction but are not particularly limited. The deprotectionreaction is usually carried out at a temperature of from 0° C. to 150°C. in a period of from 1 to 10 hours in order to lower the occurrence ofthe side reactions.

[0584] Where the amino-protecting group is an aralkyl group or anaralkyloxycarbonyl group, the protecting group is usually and preferablyremoved by treating with a reducing agent in an inert solvent(preferably by catalytic hydrogenation with a catalyst at roomtemperature) or treating with an oxidizing agent.

[0585] The solvent used in the deprotection reaction by the catalytichydrogenation is not particularly limited provided that it has noadverse effect on the reaction. Examples of suitable solvents includealiphatic hydrocarbons such as hexane, heptane, ligroin or petroleumether; aromatic hydrocarbons such as toluene, benzene or xylene; esterssuch as methyl acetate, ethyl acetate, propyl acetate, butyl acetate ordiethyl carbonate; ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; alcohols such as methanol, ethanol, n-propanol,isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve;organic acids such as acetic acid; water; or mixtures of water and oneor more organic solvents thereof. Of these solvents, alcohols, ethers,organic acids or water are preferred, and alcohols or organic acids areparticularly preferred.

[0586] The catalyst used in the deprotection reaction by catalytichydrogenation is not particularly limited provided that it is usuallyused in catalytic hydrogenation. Examples of preferable catalysts usedin catalytic hydrogenation include palladium-on-charcoal, Raney nickel,platinum oxide, platinum black, rhodium-aluminium oxide,triphenylphosphine-rhodium chloride and palladium-barium sulfate.

[0587] The pressure in catalytic hydrogenation is not particularlylimited, but the deprotection by catalytic hydrogenation is usuallycarried out at a pressure of from 1 to 10 atmospheric pressure.

[0588] The reaction temperature and reaction time mainly depend on thestarting material compounds, the catalyst and the solvent employed inthe reaction. The deprotection reaction is usually carried out at atemperature of from 0° C. to 100° C. in a period of from 5 minutes to 24hours.

[0589] The solvent used in the deprotection by oxidation reaction is notparticularly limited provided that it has no adverse effect on thereaction. This reaction is preferably carried out in an organic solventcontaining water.

[0590] Examples of the preferable organic solvent used in this reactioninclude halogenated hydrocarbons such as chloroform, methylene chloride,1,2-dichloroethane or carbon tetrachloride; nitriles such asacetonitrile; ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; ketones such as acetone; amides such as formamide,dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide;sulfoxides such as dimethyl sulfoxide; or sulfolane. Halogenatedhydrocarbons, ethers or sulfoxides (particularly halogenatedhydrocarbons or sulfoxides) are preferable.

[0591] The oxidizing agent used in this reaction is not particularlylimited provided that it is usually used for oxidation reactions.Examples of the preferable oxidizing agents used in this reactioninclude potassium persulfate, sodium persulfate, ammonium cerium nitrate(CAN) and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ).

[0592] The reaction temperature and reaction time mainly depend on thestarting material compounds, the catalyst and the soluvent employed inthe reaction. The deprotection reaction is usually carried out at atemperature of from 0° C. to 150° C. in a period of from 10 minutes to24 hours.

[0593] Alternatively, where the amino-protecting group is an aralkylgroup, the protecting group may be removed using an acid.

[0594] The acid used in the above-mentioned reaction is not particularlylimited provided that it is usually used as the acid catalyst in commonreactions. Examples of a suitable acid include Brönsted acids includinginorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, perchloric acid or phosphoric acid; or organic acids such asacetic acid, formic acid, oxalic acid, methanesulfonic acid,p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid ortrifluoromethanesulfonic acid; Lewis acids such as zinc chloride, tintetrachloride, boron trichloride, boron trifluoride or boron tribromide;and acidic ion-exchange resins. Inorganic and organic acids (mostpreferably hydrochloric acid, acetic acid or trifluoroacetic acid) arepreferable.

[0595] The inert solvent used in the first stage of the above-mentionedreaction is not particularly limited provided that it has no adverseeffect on the reaction. Examples of suitable solvents include aliphatichydrocarbons such as hexane, heptane, ligroin or petroleum ether;aromatic hydrocarbons such as benzene, toluene or xylene; halogenatedhydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethaneor carbon tetrachloride; esters such as methyl acetate, ethyl acetate,propyl acetate, butyl acetate or diethyl carbonate; ethers such asdiethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane or di(ethylene glycol) dimethyl ether; alcohols such asmethanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol,t-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol,glycol) dimethyl ether; alcohols such as methanol, ethanol, n-propanol,isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,diethylene glycol, glycerol, octanol, solvents thereof or of solventsthereof. Of these solvents, ethers, alcohols or water (most preferablydioxane, tetrahydrofuran, ethanol or water) are preferred.

[0596] The reaction temperature mainly depends on the starting materialcompounds, the acid and the solvent employed in the reaction. Thereaction is usually carried out at a temperature of from −20° C. to theboiling point of the solvent used (preferably from 0° C. to 100° C.).

[0597] The reaction time mainly depends on the starting materialcompounds, the acid, the solvent and the reaction temperature employedin the reaction. The reaction is usually carried out in a period of from15 minutes to 48 hours (preferably from 30 minutes to 20 hours).

[0598] Where the amino-protecting group is an alkenyloxycarbonyl group,the deprotection reaction is usually carried out by treating with a baseunder the same reaction conditions as that described for thedeprotection of the amino group protected with an aliphatic acyl group,an aromatic acyl group, an alkoxycarbonyl group or a substitutedmethylene group which forms a Schiff base.

[0599] Where the amino-protecting group is an allyoxycarbonyl group,however, the deprotection is commonly carried out by catalytichydrogenation using a palladium, triphenylphosphine or nickeltetracarbonyl derivative, since this deprotection procedure is simpleand the occurrence of side reactions is low.

[0600] Where the hydroxyl-protecting group is a silyl group, theprotecting group is usually removed by treating with a compound fromwhich a fluorine anion is generated, such as tetrabutylammoniumfluoride, hydrofluoric acid, hydrofluoric acid-pyridine and potassiumfluoride or by treating with an inorganic acid such as hydrochloricacid, hydrobromic acid, sulfuric acid, perchloric acid or phosphoricacid; or an organic acid such as acetic acid, formic acid, oxalic acid,methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid,trifluoroacetic acid or trifluoromethanesulfonic acid.

[0601] In some cases of the removal of the protecting group by afluorine anion, the reaction is accelerated by the addition of anorganic acid such as formic acid, acetic acid or propionic acid.

[0602] The inert solvent used in the above-mentioned reaction is notparticularly limited provided that it has no adverse effect on thereaction. Examples of preferable solvents include ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordi(ethylene glycol) dimethyl ether; nitriles such as acetonitrile orisobutyronitrile; organic acids such as acetic acid; water; or mixturesof solvents thereof.

[0603] The reaction temperature and reaction time mainly depend on thestarting material compound, the catalyst and the solvent employed in thereaction. The reaction is usually carried out at a temperature of from0° C. to 100° C. (preferably from 10° C. to 50° C.) in a period of from1 to 24 hours.

[0604] Where the hydroxyl-protecting group is an aralkyl group or anaralkyloxycarbonyl group, the protecting group is usually and preferablyremoved by treating with a reducing agent (preferably by catalytichydrogenatin with a catalyst at room temperature) in an inert solvent orby treating with an oxidizing agent.

[0605] The solvent used in the deprotection reaction by catalytichydrogenation is not particularly limited provided that it has noadverse effect on the reaction. Examples of suitable solvents includealiphatic hydrocarbons such as hexane, heptane, ligroin or petroleumether; aromatic hydrocarbons such as toluene, benzene or xylene; esterssuch as ethyl acetate or propyl acetate; ethers such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordi(ethylene glycol) dimethyl ether; alcohols such as methanol, ethanol,n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamylalcohol, diethylene glycol, dimethoxyethane or di(ethylene glycol)dimethyl ether; alcohols such as methanol, ethanol, n-propanol,isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,diethylene glycol, triamide; aliphatic acids such as formic acid oracetic acid; water; or mixtures of solvents thereof. Of these solvents,alcohols (particularly methanol) are preferred.

[0606] The catalyst used in the deprotection reaction by catalytichydrogenation is not particularly limited provided that it is usuallyused in catalytic hydrogenation. Examples of suitable catalysts used inthe catalytic hydrogenation include palladium-on-charcoal, palladiumblack, Raney nickel, platinum oxide, platinum black, rhodium-aluminiumoxide, triphenylphosphine-rhodium chloride and palladium-barium sulfate,and palladium-on-charcoal is preferred.

[0607] The pressure in the catalytic hydrogenation is not particularlylimited, but the deprotection by catalytic hydrogenation is usuallycarried out at a pressure of from 1 to 10 atmospheric pressure.

[0608] The reaction temperature and reaction time mainly depend on thestarting material compound, the catalyst and the solvent employed in thereaction. The deprotection reaction is usually carried out at atemperature of from 0° C. to 100° C. in a period of from 5 minutes to 48hours, and preferably carried out at a temperature of from 20° C. to 70°C. in a period of from 1 to 24 hours.

[0609] The solvent used in the deprotection by oxidation reaction is notparticularly limited provided that it has no adverse effect on thereaction. This reaction is preferably carried out in an organic solventcontaining water.

[0610] Examples of the preferable organic solvent used in this reactioninclude ketones such as acetone; halogenated hydrocarbons such asmethylene chloride, chloroform or carbon tetrachloride; nitriles such asacetonitrile; ethers such as diethyl ether, tetrahydrofuran or dioxane;amides such as dimethylformamide, dimethylacetamide orhexamethylphosphoric triamide; or sulfoxides such as dimethyl sulfoxide.

[0611] The oxidizing agent used in this reaction is not particularlylimited provided that it is usually used for oxidation reactions.Examples of the preferable oxidizing agents used in this reactioninclude potassium persulfate, sodium persulfate, ammonium cerium nitrate(CAN) and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ).

[0612] The reaction temperature and reaction time mainly depend on thestarting material compound, the catalyst and the solvent employed in thereaction. The deprotection reaction is usually carried out at atemperature of from 0° C. to 150° C. in a period of from 10 minutes to24 hours. Alternatively, the protecting group can also be removed bytreating with alkali metals such as metallic lithium or metallic sodiumat a temperature of from −78° C. to 0° C. in liquid ammonia. or alcoholsuch as methanol, ethanol, n-propanol, isopropanol, n-butanol,isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerol,octanol, cyclohexanol or methyl cellosolve.

[0613] Additionally, the protecting group can also be removed bytreating with aluminium chloride-sodium iodide or an alkylsilyl halidesuch as trimethylsilyl iodide in a solvent.

[0614] The solvent used in the deprotection reaction is not particularlylimited provided that it has no adverse effect on the reaction. Examplesof the preferable solvents used in this reaction include halogenatedhydrocarbons such as methylene chloride, chloroform or carbontetrachloride; nitriles such as acetonitrile; or mixtures of solventsthereof.

[0615] The reaction temperature and reaction time mainly depend on thestarting material compound and the solvent employed in the reaction. Thedeprotection reaction is usually carried out at a temperature of from 0°C. to 50° C. in a period of from 5 minutes to 72 hours.

[0616] Where a sulfur atom is contained in a compound subjected to thedeprotection reaction, aluminium chloride-sodium iodide is preferablyused.

[0617] Where the hydroxyl-protecting group is an aliphatic acyl group,an aromatic acyl group or an alkoxycarbonyl group, the protecting groupis removed by treating with a base in a solvent. The base that can beused in the above-described reaction is not particularly limitedprovided that it has no adverse effect on the structural moieties otherthan the protection group. Examples of preferable bases include alkalimetal carbonates such as lithium carbonate, sodium carbonate orpotassium carbonate; alkali metal bicarbonates such as lithiumbicarbonate, sodium bicarbonate or potassium bicarbonate; alkali metalhydroxides such as lithium hydroxide, sodium hydroxide or potassiumhydroxide; alkali metal alkoxides such as lithium methoxide, sodiummethoxide, sodium ethoxide or potassium t-butoxide; or ammonia solutionssuch as ammonia solution or concentrated methanolic ammonia solution.Alkali metal hydroxides, alkali metal alkoxides or ammonia solutions arepreferred, and alkali metal hydroxides and alkali metal alkoxides areparticularly preferred.

[0618] The solvent used in the above-mentioned reaction is notparticularly limited provided that it is usually used in hydrolysisreactions. Examples of preferable solvents include ethers such asdiethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane or di(ethylene glycol) dimethyl ether; alcohols such asmethanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol,t-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol,cyclohexanol or methyl cellosolve; water; or mixtures of solventsthereof.

[0619] The reaction temperature and reaction time mainly depend on thestarting material compounds, the base and the solvent employed in thereaction but are not particularly limited. The deprotection reaction isusually carried out at a temperature of from −20° C. to 150° C. in aperiod of from 1 to 10 hours in order to lower the occurrence of theside reactions.

[0620] Where the hydroxyl-protecting group is any of an alkoxymethylgroup, tetrahydropyranyl group, tetrahydrothiopyranyl group,tetrahydrofuranyl group, tetrahydrothiofuranyl group or substitutedethyl group, the protecting group is usually removed by treating with anacid in a solvent.

[0621] The acid used in this reaction is not particularly limitedprovided that it is usually used as a Brønsted acid or Lewis acid.Examples of preferable Brønsted acids include inorganic acids such ashydrogen chloride, hydrochloric acid, sulfuric acid or nitric acid ororganic acids such as acetic acid, trifluoroacetic acid, methanesulfonicacid or p-toluenesulfonic acid, and examples of preferable Lewis acidsinclude boron trifluoride. Additionally, strongly acidic cation exchangeresins such as Dowex 50W can be also used.

[0622] The solvent used in the above-mentioned reaction is notparticularly limited provided that it has no adverse effect on thereaction. Examples of suitable solvents include aliphatic hydrocarbonssuch as hexane, heptane, ligroin or petroleum ether; aromatichydrocarbons such as benzene, toluene or xylene; halogenatedhydrocarbons such as methylene chloride, chloroform, carbontetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; esterssuch as ethyl formate, ethyl acetate, propyl acetate, butyl acetate ordiethyl carbonate; ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; alcohols such as methanol, ethanol, n-propanol,isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve;ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone,isophorone or cyclohexanone; water; or mixtures of solvents thereof. Ofthese solvents, ethers (particularly tetrahydrofuran) and alcohols(particularly methanol) are preferred.

[0623] The reaction temperature and reaction time mainly depend on thestarting material compounds, the acid and the solvent employed in thereaction. The reaction is usually carried out at a temperature of from−10° C. to 200° C. (preferably from 0° C. to 150° C.) in a period offrom 5 minutes to 48 hours (preferably from 30 minutes to 10 hours).

[0624] Where the hydroxyl-protecting group is an alkenyloxycarbonylgroup, the deprotection reaction is usually carried out by treating witha base under the same reaction conditions as that described for thedeprotection of the hydroxyl group protected with an aliphatic acylgroup, an aromatic acyl group or an alkoxycarbonyl group.

[0625] Where the hydroxyl-protecting group is an allyloxycarbonyl group,however, the deprotection reaction is usually and preferably carried outby a catalytic hydrogenation using palladium, triphenylphosphine orbis(methyldiphenylphosphine)(1,5-cyclooctadiene)iridium (I)hexafluorophosphate, since this procedure is simple and the occurrenceof side reactions is low.

[0626] Where the carboxyl-protecting group is a C₁-C₆ alkyl group or aC₁-C₆ alkyl group substituted with one to three C₆-C₁₀ aryl substituentswhich is optionally substituted with C₁-C₆ alkyl, C₁-C₁₀ alkoxy, nitro,halogen or cyano, the deprotection reaction is usually carried out bytreatment with a base under the same reaction conditions as thatdescribed for the deprotection of the hydroxyl group protected with analiphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group.

[0627] In addition, the removal of the amino-, the hydroxyl- and/or thecarboxyl-protecting groups can be carried out by conducting the suitabledeprotection reactions successively without any special order, ifnecessary.

[0628] The procedures for protecting the amino group and the hydroxylgroup depend on the nature of the protecting group used, but theprotection is generally carried out according to the known procedurescommonly used in organic synthetic chemistry as shown below.

[0629] In the case of a compound (I) where R¹ and R² are each a hydrogenatom, the protection of the amino group can be carried out by thereaction of the relevant compound with a compound of general formula(XII) shown below in an inert solvent (examples of a preferable solventinclude ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; or alcohols such as methanol, ethanol, n-propanol,isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve)in the presence or absence of a base (organic amines such astriethylamine, tributylamine, diisopropylethylamine, N-methylmorpholineor pyridine) at a temperature of from 0° C. to 50° C. (preferably atroom temperature) in a period of from 30 minutes to 10 hours (preferablyfrom 1 to 5 hours).

R^(1a)-Z   (XII)

[0630] [in the formula, R^(1a) is an amino-protecting group (as definedearlier) and Z is a halogen atom]

[0631] In the case of a compound (I) where R³ is a hydrogen atom, theprotection of the hydroxyl group can be carried out by the reaction ofthe relevant compound with a compound of general formula (XIII) shownbelow in an inert solvent (examples of a preferable solvent includehalogenated hydrocarbons such as chloroform, methylene chloride,1,2-dichloroethane or carbon tetrachloride; amides such as formamide,dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide;or sulfoxides such as dimethylsulfoxide) in the presence of a base(examples of a preferable base include alkali metal hydrides such aslithium hydride, sodium hydride or potassium hydride; and organic aminessuch as triethylamine, tributylamine, diisopropylethylamine,N-methylmorpholine or pyridines) at a temperature of from 0° C. to 50°C. (preferably at around room temperature) in a period of from 30minutes to 24 hours (preferably from 1 to 24 hours).

R^(3a)-Z   (XIII)

[0632] [in the formula, R^(3a) is a hydroxyl-protecting group (asdefined earlier) and Z is as defined earlier]

[0633] Furthermore, the removal of the amino-, the hydroxyl- and/or thecarboxyl-protecting groups and the protection of the amino group, thehydroxyl group and/or the carboxyl group can be carried out byconducting the suitable deprotection or protection reactionssuccessively without any special order, if necessary.

[0634] After the completion of the reaction, the target compounds (I) ofthis reaction may be collected from the reaction mixture according tothe conventional method. For example, the target compound can beobtained by conducting the following steps successively: appropriatelyneutralizing the reaction mixture; removing, if any, insolublematerial(s) by filtration; adding an organic solvent which is notmiscible with water (e.g. ethyl acetate); separating the organic layercontaining the target compound; washing the extract with, for example,water and then drying over anhydrous magnesium sulfate, anhydrous sodiumsulfate, anhydrous sodium bicarbonate or the like; and removing solventby evaporation. The target compound can be isolated and purified, ifnecessary, by a suitable combination of conventional methods commonlyused for the separation/purification of organic compounds such asrecrystallization, reprecipitation and chromatography using appropriateeluent(s).

[0635] In Step A9, a compound of general formula (I) is synthesized byhydrolyzing a compound (X) with a base and then, if necessary, byconducting successively the removal of an amino, a hydroxyl- and/or acarboxyl-protecting group in R¹, R², R³, R^(5a), R^(6a) and R^(7a), theprotection of an amino group in R¹ and/or R², and/or the protection of ahydroxyl group in R³. This step is carried out in a similar manner tothat described earlier in Step A8 of the method A.

[0636] In Step A10, a compound of general formula (Ic) is synthesized byreducing the ester group of a compound (IX) and then, if necessary, byconducting successively the removal of an amino, a hydroxyl- and/or acarboxyl-protecting group in R¹, R², R³, R^(5a), R^(6a) and R^(7a), theprotection of an amino group in R¹ and/or R², and/or the protection of ahydroxyl group in R³. The reduction of the ester group of the compound(IX) is carried out in a similar manner to that described earlier inStep A6 of the method A.

[0637] In Method B, a compound (Id) which is a compound (I) where X isan ethynylene group, a compound (Ie) which is a compound (I) where X isa vinylene group, a compound (If) which is a compound (I) where X is anethylene group, a compound (Ig) which is a compound (I) where X is a“—CO—CH₂—” group, a compound (Ig-1) which is a compound (I) where X is a“—CO—CH₂—” group and R¹ is a “—CO₂R¹⁰” group, a compound (Ih) which is acompound (I) where X is a “—CH(OH)—CH₂—” group, a compound (Ii) which isa compound (I) where X is an aryl group or an aryl group substitutedwith 1-3 substituents selected-from the substituent group a, and acompound (Ij) which is a compound (I) where X is an oxygen atom or asulfur atom are prepared.

[0638] In the above scheme, R¹, R², R³, R⁴, R⁵, R^(5a), R⁶, R^(6a), R⁷,R^(7a), R¹⁰, Y and n are as defined earlier, X_(a) is an oxygen atom ora sulfur atom, Y_(a) is a C₁-C₁₀ alkylene group or a C₁-C₁₀ alkylenegroup substituted with 1-3 substituents selected from the substituentgroups a and b, ring A is an aryl group or an aryl group substitutedwith 1-3 substituents selected from the substituent group a, and W is agroup having the following general formulae.

[0639] [in the above formulae, R⁴ and R¹⁰ are as defined earlier, R′ andR″ are the same or different and each is independently a lower alkylgroup, an aryl group or an aryl group substituted with 1-3 substituentsselected from the substituent group a].

[0640] In Step B1, a compound of general formula (XVI) is synthesized bythe Sonogashira coupling reaction of a compound of general formula (XIV)and a compound of general formula (XV) in an inert solvent in thepresence of a base and palladium catalyst.

[0641] The solvent used in the above-mentioned reaction is notparticularly limited provided that it has no adverse effect on thereaction. Examples of suitable solvents include aliphatic hydrocarbonssuch as hexane, heptane, ligroin or petroleum ether; aromatichydrocarbons such as benzene, toluene or xylene; halogenatedhydrocarbons such as methylene chloride, chloroform, carbontetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; esterssuch as ethyl formate, ethyl acetate, propyl acetate, butyl acetate ordiethyl carbonate; ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; ketones such as acetone, methyl ethyl ketone, methylisobutyl ketone, isophorone or cyclohexanone; nitriles such asacetonitrile or isobutyronitrile; amides such as formamide,dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide;and sulfoxides such as dimethyl sulfoxide or sulfolane. Ethers, amidesor sufoxides (particularly amides or ethers) are preferable. In somecases, the reaction is accelerated by the addition of a small amount ofwater to the reaction solvent.

[0642] The base used in the above-mentioned reaction is, for example,the same as that used for the conversion of the hydroxyl group into theleaving group described in Step A2 of the method A, and organic amines(most preferably triethylamine) are preferred.

[0643] The palladium catalyst used in the above-mentioned reaction isnot particularly limited provided that it is usually used for theSonogashira coupling reaction. Examples of the preferred catalystsinclude palladium salts such as palladium acetate, palladium chloride orpalladium carbonate; and palladium complexes such asbis(triphenylphosphine)palladium chloride complex formed from complexeswith ligands.

[0644] Furthermore, the yield can be improved by the addition of cuprouschloride or benzyltriethylammonium chloride as an additive.

[0645] The reaction temperature mainly depends on the starting materialcompounds, the base and the solvent employed in the reaction. Thereaction is usually carried out at a temperature of from −20° C. to 200°C. (preferably from 0° C. to 120° C.).

[0646] The reaction time mainly depends on the starting materialcompounds, the base, the solvent and the reaction temperature employedin the reaction. The reaction is usually carried out in a period of from5 minutes to 48 hours (preferably from 15 minutes to 24 hours).

[0647] After the completion of the reaction, the target compounds (XVI)of this reaction may be collected from the reaction mixture according toconventional methods. For example, the target compound can be obtainedby conducting the following steps successively: appropriatelyneutralizing the reaction mixture; removing, if any, insolublematerial(s) by filtration; adding an organic solvent which is notmiscible with water (e.g. ethyl acetate); separating the organic layercontaining the target compound; washing the extract with, for example,water and then drying over anhydrous magnesium sulfate, anhydrous sodiumsulfate, anhydrous sodium bicarbonate or the like; and removing solventby evaporation. The target compound can be isolated and purified, ifnecessary, by a suitable combination of the conventional methodscommonly used for the separation/purification of organic compounds suchas recrystallization, reprecipitation and chromatography usingappropriate eluent(s).

[0648] In Step B2, a compound of general formula (Id) is prepared asfollows. Where W of a compound (XVI) is a (W-1) group, the compound ofgeneral formula (Id) is synthesized in a similar manner to thatdescribed either in steps A7 and A8 of the method A or step A9 of themethod A. On the other hand, where W of a compound (XVI) is a (W-2)group or a (W-3) group, the compound (Id) is prepared in a similarmanner to that described earlier in step A8 of the method A.

[0649] In Step B3, a compound of general formula (XVII) is prepared byconducting the reaction of a compound (XV) with catecholborane andsubsequently by conducting the Suzuki coupling reaction of the resultingproduct and a compound (XIV).

[0650] The reaction temperature for the reaction of the compound (XV)with catecholborane mainly depends on the starting material compounds,the base and the solvent employed in the reaction. The reaction isusually carried out at a temperature of from 0° C. to 150° C.(preferably from 10° C. to 100° C.).

[0651] The reaction time for the reactions of the compound (XV) withcatecholborane mainly depends on the starting material compounds, thebase, the solvent and the reaction temperature employed in the reaction.The reaction is usually carried out in a period of from 15 minutes to 24hours (preferably from 30 minutes to 12 hours).

[0652] The Suzuki coupling reaction is carried out in a similar mannerto that described for the Sonogashira coupling reaction in step B1 ofthe method B.

[0653] The solvent used in the above-mentioned reaction is the same asthat used in Step B1 of the method B, and aromatic hydrocarbons (mostpreferably toluene) are preferred.

[0654] The base used in the above-mentioned reaction is, for example,the same as that used for the conversion of the hydroxyl group into theleaving group described in Step A2 of the method A, and alkali metalalkoxides (most preferably sodium ethoxide) are preferred.

[0655] The palladium catalyst used in the above-mentioned reaction isthe same as that used in Step B1 of the method B, and palladiumcomplexes (most preferably bis(triphenylphosphine)palladium chloridecomplex) are preferred.

[0656] In Step B4, a compound of general formula (Ie) is prepared asfollows. Where W of a compound (XVII) is a (W-1) group, the compound ofgeneral formula (Ie) is synthesized in a similar manner to thatdescribed either in steps A7 and A8 of the method A or step A9 of themethod A. On the other hand, where W of a compound (XVII) is a (W-2)group or a (W-3) group, the compound (Ie) is prepared in a similarmanner to that described earlier in step A8 of the method A.

[0657] In Step B5, a compound of general formula (XVIII) is prepared byreducing a compound (XVI) in an inert solvent (preferably a catalytichydrogenation at room temperature in the presence of a catalyst).

[0658] The solvent used in the deprotection by the catalytichydrogenation is not particularly limited provided that it has noadverse effect on the reaction. Examples of suitable solvents includealiphatic hydrocarbons such as hexane, heptane, ligroin or petroleumether; aromatic hydrocarbons such as toluene, benzene or xylene;halogenated hydrocarbons such as methylene chloride, chloroform, carbontetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; esterssuch as methyl acetate, ethyl acetate, propyl acetate, butyl acetate ordiethyl carbonate; ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; alcohols such as methanol, ethanol, n-propanol,isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve;organic acids such as acetic acid or hydrochloric acid; water; ormixtures of water and solvents thereof. Of these solvents, alcohols andethers (particularly methanol) are preferred.

[0659] The catalyst used in the deprotection by the catalytichydrogenation is not particularly limited provided that it is usuallyused in catalytic hydrogenation. Examples of preferred catalysts used incatalytic hydrogenation include palladium-on-charcoal, Raney nickel,platinum oxide, platinum black, rhodium-aluminium oxide,triphenylphosphine-rhodium chloride and palladium-barium sulfate.

[0660] The reaction temperature mainly depends on the starting materialcompounds, the base and the solvent employed in the reaction. Thereaction is usually carried out at a temperature of from −20° C. to 200°C. (preferably from 0° C. to 100° C.).

[0661] The reaction time mainly depends on the starting materialcompounds, the base, the solvent and the reaction temperature employedin the reaction. The reaction is usually carried out in a period of from5 minutes to 96 hours (preferably from 15 minutes to 72 hours).

[0662] After the completion of the reaction, the target compounds(XVIII) of this reaction may be collected from the reaction mixtureaccording to conventional methods. For example, the target compound canbe obtained by conducting the following steps successively:appropriately neutralizing the reaction mixture; removing, if any,insoluble material(s) by filtration; adding an organic solvent which isnot miscible with water (e.g. ethyl acetate); separating the organiclayer containing the target compound; washing the extract with, forexample, water and then drying over anhydrous magnesium sulfate,anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; andremoving solvent by evaporation. The target compound can be isolated andpurified, if necessary, by a suitable combination of the conventionalmethods commonly used for the separation/purification of organiccompounds such as recrystallization, reprecipitation and chromatographyusing appropriate eluent(s).

[0663] In Step B6, a compound of general formula (If) is prepared asfollows. Where W of a compound (XVIII) is a (W-1) group, the compound ofgeneral formula (If) is synthesized in a similar manner to thatdescribed either in steps A7 and A8 of the method A or step A9 of themethod A. On the other hand, where W of a compound (XVIII) is a (W-2)group or a (W-3) group, the compound (If) is prepared in a similarmanner to that described earlier in step A8 of the method A.

[0664] In Step B7, a compound of general formula (XIX) is prepared asfollows. Where W of a compound (XVI) is a (W-1) group, the compound ofgeneral formula (XIX) is synthesized in a similar manner to thatdescribed either in steps A7 and A8 of the method A or step A9 of themethod A. On the other hand, where W of a compound (XVI) is a (W-2)group or a (W-3) group, the compound (XIX) is prepared in a similarmanner to that described earlier in step A8 of the method A.

[0665] In Step B8, a compound of general formula (Ig) is prepared bytreating a compound (XIX) in an inert solvent by procedures comprisingthe addition reaction of water in the presence of an acid catalyst orthe oxymercuration reaction with mercury oxide and then, if necessary,by conducting successively the removal of-an amino-, a hydroxyl- and/ora carboxyl-protecting group in R¹, R², R³, R^(5a), R^(6a) and R^(7a),the protection of an amino group in R¹ and/or R², and/or the protectionof a hydroxyl group in R³.

[0666] The solvent used in the above-mentioned reaction is notparticularly limited provided that it has no adverse effect on thereaction. Examples of suitable solvents include aliphatic hydrocarbonssuch as hexane, heptane, ligroin or petroleum ether; aromatichydrocarbons such as benzene, toluene or xylene; halogenatedhydrocarbons such as methylene chloride, chloroform, carbontetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; esterssuch as ethyl formate, ethyl acetate, propyl acetate, butyl acetate ordiethyl carbonate; ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; alcohols such as methanol, ethanol, n-propanol,isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve;ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone,isophorone, cyclohexanone; water; or mixtures of solvents thereof. Ofthese solvents, alcohols (particularly methanol) are preferred.

[0667] The acid catalyst used in the above-mentioned reaction is notparticularly limited provided that it is usually used as an acidcatalyst in common reactions. Examples of suitable acids includeBrönsted acids including inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, perchloric acid or phosphoric acid; andorganic acids such as acetic acid, formic acid, oxalic acid,methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid,trifluoroacetic acid or trifluoromethanesulfonic acid; Lewis acids suchas zinc chloride, tin tetrachloride, boron trichloride, borontrifluoride or boron tribromide; and acidic ion-exchange resins.Inorganic acids (most preferably sulfuric acid) are preferable.

[0668] The reaction temperature mainly depends on the starting materialcompounds, the base and the solvent employed in the reaction. Thereaction is usually carried out at a temperature of from −20° C. to 200°C. (preferably from 0° C. to 100° C.).

[0669] The reaction time mainly depends on the starting materialcompounds, the base, the solvent and the reaction temperature employedin the reaction. The reaction is usually carried out in a period of from5 minutes to 96 hours (preferably from 15 minutes to 72 hours).

[0670] The removal of an amino-, a hydroxyl- and/or acarboxyl-protecting group in R¹, R², R³, R^(5a), R^(6a) and R^(7a), theprotection of an amino group in R¹ and/or R², and/or the protection of ahydroxyl group in R³, all of which are, if necessary, carried out, areperformed in a similar manner to that described in step A8 of the methodA.

[0671] In Step B9, a compound of general formula (Ig-1) is prepared bytreating a compound (XVIa) in an inert solvent by procedures comprisingthe addition reaction of water in the presence of an acid catalyst orthe oxymercuration reaction with mercury oxide and then, if necessary,by conducting successively the removal of an amino-, a hydroxyl- and/ora carboxyl-protecting group in R¹, R², R³, R^(5a), R^(6a) and R^(7a),and/or the protection of a hydroxyl group in R³. This step is carriedout in a similar manner to that described earlier in Step B8 of themethod B.

[0672] In Step B10, a compound of general formula (XX) is prepared bytreating a compound (XIX) in an inert solvent by procedures comprisingthe addition reaction of water in the presence of an acid catalyst orthe oxymercuration reaction with mercury oxide and then, if necessary,by conducting successively the removal of an amino-, a hydroxyl- and/ora carboxyl-protecting group in R¹, R², R³, R^(5a), R^(6a) and R^(7a),the protection of an amino group in R¹ and/or R², and/or the protectionof a hydroxyl group in R³. This step is carried out in a similar mannerto that described earlier in Step B8 of the method B.

[0673] In Step B11, a compound of general formula (Ih) is synthesized byreducing a compound (XX) in an inert solvent and then, if necessary, byconducting successively the removal of an amino-, a hydroxyl- and/or acarboxyl-protecting group in R¹, R², R³, R^(5a), R^(6a) and R^(7a), theprotection of an amino group in R¹ and/or R², and/or the protection of ahydroxyl group in R³.

[0674] The inert solvent used in the above-mentioned reaction is notparticularly limited provided that it has no adverse effect on thereaction. Examples of suitable solvents include aliphatic hydrocarbonssuch as hexane, heptane, ligroin or petroleum ether; aromatichydrocarbons such as benzene, toluene or xylene; halogenatedhydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethaneor carbon tetrachloride; ethers such as diethyl ether, diisopropylether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; alcohols such as methanol, ethanol, n-propanol,isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve;or mixtures of solvents thereof. Of these solvents, ethers or alcohols(particularly methanol or ethanol) are preferred.

[0675] The reducing agent used in the above-mentioned reaction is, forexample, an alkali metal borohydride such as sodium borohydride, lithiumborohydride or sodium cyanoborohydride; or an aluminium hydride such asdiisobutylaluminium hydride, lithium aluminium hydride ortriethoxyaluminium lithium hydride. The preferred example is an alkalimetal borohydride (sodium cyanoborohydride).

[0676] The reaction temperature mainly depends on the starting materialcompounds, the base and the solvent employed in the reaction. Thereaction is usually carried out at a temperature of from −10° C. to 100°C. (preferably from −20° C. to 20° C.).

[0677] The reaction time mainly depends on the starting materialcompounds, the base, the solvent and the reaction temperature employedin the reaction. The reaction is usually carried out in a period of from10 minutes to 48 hours (preferably from 30 minutes to 12 hours).

[0678] The removal of an amino-, a hydroxyl- and/or acarboxyl-protecting group in R¹, R², R³, R^(5a), R^(6a) and R^(7a), theprotection of an amino group in R¹ and/or R², and/or the protection of ahydroxyl group in R³, all of which are, if necessary, carried out, areperformed in a similar manner to that described in step A8 of the methodA.

[0679] After the completion of the reaction, the target compounds (Ih)of this reaction may be collected from the reaction mixture according toconventional methods. For example, the target compound can be obtainedby conducting the following steps successively: appropriatelyneutralizing the reaction mixture; removing, if any, insolublematerial(s) by filtration; adding an organic solvent which is notmiscible with water (e.g. ethyl acetate); separating the organic layercontaining the target compound; washing the extract with, for example,water and then drying over anhydrous magnesium sulfate, anhydrous sodiumsulfate, anhydrous sodium bicarbonate or the like; and removing solventby evaporation. The target compound can be isolated and purified, ifnecessary, by a suitable combination of the conventional methodscommonly used for the separation/purification of organic compounds suchas recrystallization, reprecipitation and chromatography usingappropriate eluent(s).

[0680] In Step B12, a compound of general formula (XXII) is prepared byconducting the Suzuki coupling reaction of a compound (XXI) and acompound (XIV). This step is carried out in a similar manner to thatdescribed for the Sonogashira coupling reaction in Step B3 of the methodB.

[0681] In Step B13, a compound of general formula (Ii) is prepared asfollows. Where W of a compound (XXII) is a (W-1) group, the compound ofgeneral formula (Ii) is synthesized in a similar manner to thatdescribed either in steps A7 and A8 of the method A or step A9 of themethod A. On the other hand, where W of a compound (XXII) is a (W-2)group or a (W-3) group, the compound (Ii) is prepared in a similarmanner to that described earlier in step A8 of the method A.

[0682] In Step B 14, a compound of general formula (XXIV) is prepared bythe reaction of a compound (XIV) with an alkali metal salt of a compound(XXIII) under conditions without solvent or in an inert solvent in thepresence of a copper catalyst. This step is carried out by theprocedures, for example, described in J. Heterocyclic. Chem., 20, 1557(1983).

[0683] The solvent used in the above-mentioned reaction is notparticularly limited provided that it has no adverse effect on thereaction. Examples of suitable solvents include ethers such as diethylether, dioxane, tetrahydrofuran, dimethoxyethane, or di(ethylene glycol)dimethyl ether; or pyridines such as pyridine, picoline, lutidine orcollidine. The reaction is carried out preferably under conditionswithout solvent.

[0684] The copper catalyst used in the above-mentioned reaction is, forexample, cuprous iodide, cuprous bromide, cuprous oxide or cupric oxide,and cuprous oxide is preferred.

[0685] The alkali metal salt of the compound (XXIII) used in theabove-mentioned reaction is prepared by treating the compound of generalformula (XXIII) and an alkali metal or alkali metallic compound.Examples of suitable alkali metals include metallic lithium, metallicsodium or metallic potassium, and examples of suitable alkali metalliccompounds include alkali metal hydrides such as lithium hydride, sodiumhydride or potassium hydride. The alkali metal salt of the compound(XXIII) is preferably prepared using metallic sodium. Furthermore, theyield can be improved by the addition of potassium iodide as anadditive.

[0686] The reaction temperature mainly depends on the starting materialcompounds, the catalyst and the solvent employed in the reaction. Thereaction is usually carried out at a temperature of from roomtemperature to 150° C. (preferably from 60° C. to 120° C.).

[0687] The reaction time mainly depends on the starting materialcompounds, the catalyst and the solvent employed in the reaction. Thereaction is usually carried out in a period of from 1 hour to 7 days(preferably from 3 hours to 72 hours).

[0688] After the completion of the reaction, the target compounds (XXIV)of this reaction may be collected from the reaction mixture according toconventional methods. For example, the target compound can be obtainedby conducting the following steps successively: appropriatelyneutralizing the reaction mixture; removing, if any, insolublematerial(s) by filtration; adding an organic solvent which is notmiscible with water (e.g. ethyl acetate); separating the organic layercontaining the target compound; washing the extract with, for example,water and then drying over anhydrous magnesium sulfate, anhydrous sodiumsulfate, anhydrous sodium bicarbonate or the like; and removing solventby evaporation. The target compound can be isolated and purified, ifnecessary, by a suitable combination of the conventional methodscommonly used for the separation/purification of organic compounds suchas recrystallization, reprecipitation and chromatography usingappropriate eluent(s).

[0689] In Step B15, a compound of general formula (Ij) is prepared asfollows. Where W of a compound (XXIV) is a (W-1) group, the compound ofgeneral formula (Ij) is synthesized in a similar manner to thatdescribed either in steps A7 and A8 of the method A or step A9 of themethod A. On the other hand, where W of a compound (XXIV) is a (W-2)group-or a (W-3) group, the compound (Ij) is prepared in a similarmanner to that described earlier in step A8 of the method A.

[0690] In Step B16, a compound of general formula (XXVI) is prepared bythe reaction of a compound of general formula (XIV) with a compound ofgeneral formula (XXV). This step is carried out in a similar manner tothat described in Step B1 of the method B.

[0691] In Step B17, a compound (XVIb) which is a compound (XVI) where Yis a “—Y_(a)—O—” group is synthesized by condensing a compound (XXVI)and a compound of general formula (XXVII) in an inert solvent by theMitsunobu reaction.

[0692] The reagent used in the Mitsunobu reaction is not particularlylimited provided that it is commonly used in the Mitsunobu reaction.Examples of preferred reagents include combinations of azo compoundsincluding di(lower alkyl) azodicarboxylates such as diethylazodicarboxylate or diisopropyl azodicarboxylate; or azodicarbonylderivatives such as 1,1′-(azadicarbonyl)dipiperidine; and phosphinesincluding triarylphosphines such as triphenylphosphine or tri(loweralkyl)phosphines such as tri-n-butylphosphine. The combinations ofdi(lower alkyl) azodicarboxylates and triarylphosphines are morepreferred. The solvent used in the above-mentioned reaction is notparticularly limited provided that it has no adverse effect on thereaction and dissolves the starting materials to some extent. Examplesof preferred solvents include aromatic hydrocarbons such as benzene,toluene or xylene; halogenated hydrocarbons such as methylene chloride,chloroform, carbon tetrachloride, dichloroethane, chlorobenzene ordichlorobenzene; esters such as ethyl formate, ethyl acetate, propylacetate, butyl acetate or diethyl carbonate; ethers such as diethylether, diisopropyl ether, tetrahydro furan, dioxane, dimethoxyethane ordi(ethylene glycol) dimethyl ether; nitriles such as acetonitrile orisobutyronitrile; amides such as formamide, N,N-dimethylformamide,N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidindne orhexamethylphosphoric triamide; or sulfoxides such as dimethyl sulfoxideor sulfolane. Aromatic hydrocarbons and ethers are preferable. Thereaction is usually carried out at a temperature of from −20° C. to 100°C. and preferably from 0° C. to 50° C.

[0693] The reaction time mainly depends on the reaction temperature, thestarting material compounds, the reagent or the solvent employed in thereaction. The reaction is usually carried out in a period of from 10minutes to 3 days and preferably from 30 minutes to 12 hours.

[0694] After the completion of the reaction, the target compounds (XVIb)of this reaction may be collected from the reaction mixture according toconventional methods. For example, the target compound can be obtainedby conducting the following steps successively: appropriatelyneutralizing the reaction mixture; removing, if any, insolublematerial(s) by filtration; adding an organic solvent which is notmiscible with water (e.g. ethyl acetate); separating the organic layercontaining the target compound; washing the extract with, for example,water and then drying over anhydrous magnesium sulfate, anhydrous sodiumsulfate, anhydrous sodium bicarbonate or the like; and removing solventby evaporation. The target compound can be isolated and purified, ifnecessary, by a suitable combination of the conventional methodscommonly used for the separation/purification of organic compounds suchas recrystallization, reprecipitation and chromatography usingappropriate eluent(s).

[0695] Alternatively, the compounds (Id)-(Ij) may be synthesized byhydrolyzing the W group of a compound (XIV) and then by conducting thereaction of the resulting product with a compound (XV), a compound(XXI), a compound (XXIII) or a compound (XXV), respectively.

[0696] The compounds (II), (V), (VIII), (XII), (XIII), (XIV), (XV),(XXI), (XXIII), (XXV) and (XXVII) used as the starting materials areeither known compounds or can be prepared easily by known or similarmethods.

[0697] Alternatively, the compounds (II) and (XIV) used as the startingmaterials can be synthesized by the following methods.

[0698] In Method C, a compound (XIV) and a compound (XIVa) which is thecompound (XIV) having a bromine atom at the 2-position of the thiophenemoiety and a “—(CH₂)n-W” group at the 5-position of the thiophene moietyas the substituents, respectively, are prepared.

[0699] In the above scheme, R⁴, R^(6a), R^(7a), R⁸, R⁹, R^(9a), R¹⁰, nand W are as defined earlier.

[0700] In Step C1, a compound of general formula (XXIX) is prepared bythe reaction of a compound of general formula (XXVIII) with a reducingagent in an inert solvent in the presence or absence of a base(preferably in the presence of a base). This step is carried out in asimilar manner to that described in Step A1 of the method A.

[0701] In Step C2, a compound of general formula (XXX) is prepared byconverting a hydroxyl group of compound (XXIX) into a leaving group inan inert solvent in the presence of a base and then by conducting aniodination reaction on the resulting leaving group with an iodinationagent. This step is carried out in a similar manner to that described inStep A2 of the method A.

[0702] In Step C3, a compound of general formula (XXXI) is prepared bythe reaction of a compound (XXX) with a compound (V) in an inert solventin the presence of a base. This step is carried out in a similar mannerto that described in Step A3 of the method A.

[0703] In Step C4, a compound of general formula (XXXII) is prepared byhydrolyzing a compound (XXXI) with a base in an inert solvent. This stepis carried out in a similar manner to that described in Step A4 of themethod A.

[0704] Step C5 is a step for converting the carboxyl group into acarbamoyl group by the Curtius Rearrangement Reaction, and in this step,a compound of general formula (XXXIII) is synthesized by the reaction ofa compound (XXXII) with a diarylphosphoryl azide derivative such asdiphenylphosphoryl azide in an inert solvent in the presence of a baseand then by the reaction of the resulting product with a compound(VIII). This step is carried out in a similar manner to that describedin Step A5 of the method A.

[0705] In Step C6, a compound (XIV) is prepared by reducing an estergroup of a compound (XXXIII). This step is carried out in a similarmanner to that described in Step A6 of the method A.

[0706] After the completion of the reaction, the target compounds (XIV)of this reaction may be collected from the reaction mixture according toconventional methods. For example, the target compound can be obtainedby conducting the following steps successively: appropriatelyneutralizing the reaction mixture; removing, if any, insolublematerial(s) by filtration; adding an organic solvent which is notmiscible with water (e.g. ethyl acetate); separating the organic layercontaining the target compound; washing the extract with, for example,water and then drying over anhydrous magnesium sulfate, anhydrous sodiumsulfate, anhydrous sodium bicarbonate or the like; and removing solventby evaporation. The target compound can be isolated and purified, ifnecessary, by a suitable combination of the conventional methodscommonly used for the separation/purification of organic compounds suchas recrystallization, reprecipitation and chromatography usingappropriate eluent(s).

[0707] In Step C7, a compound of general formula (XXXV) is prepared bythe reaction of a compound of general formula (XXXIV) with a reducingagent in an inert solvent in the presence or absence of a base(preferably in the presence of a base). This step is carried out in asimilar manner to that described in Step A1 of the method A.

[0708] In Step C8, a compound of general formula (XXXVI) is prepared byconverting a hydroxyl group of compound (XXXV) into a leaving group inan inert solvent in the presence of a base and then by conducting aniodination reaction. This step is carried out in a similar manner tothat described in Step A2 of the method A.

[0709] In Step C9, a compound of general formula (XXXVII) is prepared bythe reaction of a compound (XXXVI) with a compound (V) in an inertsolvent in the presence of a base. This step is carried out in a similarmanner to that described in Step A3 of the method A.

[0710] In Step C10, a compound of general formula (XXXVIII) is preparedby hydrolyzing a compound (XXXVII) with a base in an inert solvent. Thisstep is carried out in a similar manner to that described in Step A4 ofthe method A.

[0711] Step C11 is a step for converting the carboxyl group into acarbamoyl group by the Curtius Rearrangement Reaction, and in this step,a compound of general formula (XXXIX) is synthesized by the reaction ofthe compound (XXXVIII) with a diarylphosphoryl azide derivative such asdiphenylphosphoryl azide in an inert solvent in the presence of a baseand then by the reaction of the resulting product with a compound(VIII). This step is carried out in a similar manner to that describedin Step A5 of the method A.

[0712] In Step C12, a compound (XL) is prepared by reducing an estergroup of a compound (XXXIX). This step is carried out in a similarmanner to that described in Step A6 of the method A.

[0713] In Step C13, a compound (XIVa) is prepared by the reaction of acompound (XL) with a brominating agent.

[0714] The solvent used in the above-mentioned reaction is notparticularly limited provided that it has no adverse effect on thereaction. Examples of suitable solvents include halogenated hydrocarbonssuch as methylene chloride, chloroform, carbon tetrachloride,dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordi(ethylene glycol) dimethyl ether;.or amides such as formamide,dimethylformamide, dimethyl acetamide or hexamethylphosphoric triamide.Amides are preferable and dimethylformamide is most preferable.

[0715] The brominating agent used in the above-mentioned reaction is notparticularly limited. Examples of suitable brominating agents includethose described in “Comprehensive Organic Transformation” (Larock, VCH,p 316-317), and N-bromosuccinimide or bromine is preferred.

[0716] The reaction temperature mainly depends on the starting materialcompounds, the brominating agent and the solvent employed in thereaction. The reaction is usually carried out at a temperature of from−78° C. to 150° C. and preferably from −20° C. to 100° C.

[0717] The reaction time mainly depends on the starting materialcompounds, the brominating agent, the solvent and the reactiontemperature employed in the reaction. The reaction is usually carriedout in a period of from 5 minutes to 48 hours and preferably from 30minutes to 24 hours.

[0718] After the completion of the reaction, the target compounds (XIVa)of this reaction may be collected from the reaction mixture according toconventional methods. For example, the target compound can be obtainedby conducting the following steps successively: appropriatelyneutralizing the reaction mixture; removing, if any, insolublematerial(s) by filtration; adding an organic solvent which is notmiscible with water (e.g. ethyl acetate); separating the organic layercontaining the target compound; washing the extract with, for example,water and then drying over anhydrous magnesium sulfate, anhydrous sodiumsulfate, anhydrous sodium bicarbonate or the like; and removing solventby evaporation. The target compound can be isolated and purified, ifnecessary, by a suitable combination of the conventional methodscommonly used for the separation/purification of organic compounds suchas recrystallization, reprecipitation and chromatography usingappropriate eluent(s).

[0719] In Method D, a compound (IIa) which is a compound (II) where X isan ethyhylene group, a compound (IIb) which is a compound (II) where Xis an ethylene group, a compound (IIc) which is a compound (II) where Xis a vinylene group, a compound (IId) which is a compound (II) where Xis a “—CO—CH₂—” group, a compound (IIe) which is a compound (II) where Xis a “—CH(OH)—CH₂—” group, a compound (IIf) which is a compound (II)where X is an aryl group or an aryl group substituted with 1-3substituents selected from the substituting moieties a, and a compound(IIg) which is a compound (II) where X is an oxygen atom or a sulfuratom are prepared.

[0720] In the above scheme, R^(5a), R^(6a), R^(7a), R⁸, n, X_(a), Y,Y_(a) and ring A are as defined earlier.

[0721] In Step D1, a compound (IIa) is synthesized by the Sonogashiracoupling reaction of a compound (XXVIII) and a compound (XV) in an inertsolvent in the presence of a base and palladium catalyst. This step iscarried out in a similar manner to that described earlier in Step B1 ofthe method B.

[0722] In Step D2, a compound (IIb) is prepared by reducing a compound(IIa) in an inert solvent (preferably by a catalytic hydrogenation atroom temperature in the presence of a catalyst). This step is carriedout in a similar manner to that described earlier in Step B5 of themethod B.

[0723] In Step D3, a compound (IIc) is prepared by conducting thereaction of a compound (XV) with catecholborane and subsequently byconducting the Suzuki coupling reaction of the resulting product and acompound (XXVIII). This step is carried out in a similar manner to thatdescribed earlier in Step B3 of the method B.

[0724] In Step D4, a compound (IId) is prepared by treating a compound(IIa) in an inert solvent by procedures comprising the addition reactionof water in the presence of an acid catalyst or the oxymercurationreaction with mercury oxide. This step is carried out in a similarmanner to that described earlier in Step B8 of the method B.

[0725] In Step D5, a compound (IIe) is prepared by reducing a compound(IId) in an inert solvent. This step is carried out in a similar mannerto that described earlier in Step B11 of the method B.

[0726] In Step D6, a compound (IIf) is synthesized by conducting theSuzuki coupling reaction of a compound (XXI) and a compound (XXVIII).This step is carried out in a similar manner to that described earlierin Step B3 of the method B.

[0727] In Step D7, a compound (IIg) is prepared by conducting thereaction of a compound (XXVIII) with an alkali metal salt of a compound(XXIII) under conditions without solvent or in an inert solvent in thepresence of a copper catalyst. This step is carried out in a similarmanner to that described earlier in Step B14 of the method B.

[0728] In Step D8, a compound of general formula (XLI) is prepared bythe reaction of a compound (XXVIII) with a compound (XXV). This step iscarried out in a similar manner to that described earlier in Step B1 ofthe method B.

[0729] In Step D9, a compound (IIa-1) which is a compound (IIa) where Yis a “—Y_(a)—O—” group is prepared by the reaction of a compound (XLI)with a compound (XXVII). This step is carried out in a similar manner tothat described earlier in Step B17 of the method B.

[0730] In Method E, compounds (XLIVa), (XLIVb), (La) and (Lb), all ofwhich are an intermediate of the compound (I) of the present invention,are prepared.

[0731] In the above scheme, R¹, R², R³, R^(4a), R¹¹, Ar, m and Z are asdefined earlier.

[0732] In Step E1, a compound of general formula (XLIVa) or a compoundof general formula (XLIVb) is prepared by acylating selectively only oneof the hydroxyl groups of a compound of general formula (XLII) with acompound of general formula (XLIII) in the presence or absence of asolvent and in the presence of lipase.

[0733] The solvent used in the present invention is not particularlylimited. The reaction proceeds without any problem even when only thecompound (XLIII) is used without any solvent. In addition, a variety oforganic solvents and of mixtures of water and organic solvents can beused although the most preferred solvent in this reaction differs due tothe nature of the compound used as the starting material. Examples ofpreferred solvent include ethers such as diisopropyl ether,t-butylmethyl ether, diethyl ether or tetrahydrofuran; aliphatichydrocarbons such as n-hexane or n-pentane; aromatic hydrocarbons suchas benzene or toluene; or halogenated hydrocarbons such as methylenechloride or 1,2-dichloroethane. Ethers are preferred, and diisopropylether is most preferred.

[0734] The reaction temperature mainly depends on the starting materialcompounds, the solvent, the lipase and the nature of the compound(XLIII) employed in the reaction. The reaction is usually carried out ata temperature of from −50° C. to 50° C. and preferably from 0C to 40° C.The reaction time mainly depends on the starting material compounds, thesolvent, lipase and the nature of a compound (XLIII) employed in thereaction. The reaction is usually carried out in a period of from 15minutes to 150 hours and preferably from 30 minutes to 24 hours. Afterthe completion of the reaction, the target compounds (XLIVa) and (XLIVb)of this reaction may be collected from the reaction mixture according toconventional methods. For example, after removing, if any, insolublematerial(s) by filtration, the target compound can be obtained byconcentrating the reaction mixture or conducting the following stepssuccessively: adding an organic solvent which is not miscible with water(e.g. ethyl acetate); separating the organic layer containing the targetcompound; and then drying over anhydrous sodium sulfate, anhydrousmagnesium sulfate or the like; and removing solvent by evaporation.

[0735] The target compound obtained can be isolated and purified, ifnecessary, by conventional methods such as recrystallization,reprecipitation or chromatography using appropriate eluent(s).

[0736] In step E2, a compound of general formula (XLV) is prepared byoxidizing the alcohol moiety of a compound (XLIVa) into an aldehydemoiety in an inert solvent in the presence of an oxidizing agent.

[0737] The oxidation reaction employed in this step is not particularlylimited provided that it can be used for the preparation of the aldehydemoiety from the primary alcohol moiety. Examples of suitable reactionsinclude the Collins oxidation performed using pyridine and chromic acidin methylene chloride; PCC oxidation performed using pyridiniumchlorochromate (PCC) in methylene chloride; PDC oxidation performedusing pyridinium dichromate (PDC) in methylene chloride;Dimethylsulfoxide (DMSO) oxidation such as Swern oxidation performedusing an electrophilic agent (for example, acetic anhydride,trifluoroacetic anhydride, thionyl chloride, sulfuryl chloride, oxalylchloride, dicyclohexylcarbodiimide, diphenylketene-p-tolylimine;N,N-diethylaminoacetylene; or sulfur trioxide-pyridine complex) anddimethylsulfoxide (DMSO) in methylene chloride; and Manganese oxideoxidation performed using manganese oxide in methylene chloride orbenzene.

[0738] Of these oxidation reactions, PCC oxidation or Swern oxidationperformed in methylene chloride is preferred.

[0739] The reaction temperature mainly depends on the starting materialcompounds, the solvent and the oxidizing agent employed in the reaction.The reaction is usually carried out at a temperature of from −50° C. to50° C. and preferably from −10° C. to 30° C.

[0740] The reaction time mainly depends on the starting materialcompounds, the solvent, the oxidizing agent and the reaction temperatureemployed in the reaction. The reaction is usually carried out in aperiod of from 10 minutes to 2 days and preferably from 30 minutes to 24hours.

[0741] For example, after neutralizing the oxidizing agent with sodiumhydrogen sulfite and removing, if any, insoluble material(s) byfiltration, the target compound can be obtained by concentrating thereaction mixture or conducting the following steps successively: addingan organic solvent which is not miscible with water (e.g. ethylacetate); separating the organic layer containing the target compound;and then drying over anhydrous sodium sulfate, anhydrous magnesiumsulfate or the like; and removing solvent by evaporation.

[0742] The target compound obtained can be isolated and purified, ifnecessary, by conventional methods such as recrystallization,reprecipitation or chromatography using appropriate eluent(s).

[0743] In step E3, a compound of general formula (XLVII) is prepared bythe reaction of the aldehyde group of the compound (XLV) with a compoundof general formula (XLVI) in an inert solvent in the presence of a base.

[0744] The solvent used in the above-mentioned reaction is notparticularly limited provided that it has no adverse effect on thereaction. Examples of preferred solvents include aromatic hydrocarbonssuch as benzene, toluene or xylene; halogenated hydrocarbons such asmethylene chloride, chloroform, carbon tetrachloride,1,2-dichloroethane, chlorobenzene or dichlorobenzene; ethers such asdiethyl ether, diisopropyl ether, t-butylmethyl ether ortetrahydrofuran; nitriles such as acetonitrile or isobutyronitrile;amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide,or hexamethylphosphoric triamide; or sulfoxides such as dimethylsulfoxide or sulfolane, and ethers are more preferred.

[0745] The base used in the above reaction is not particularly limitedprovided that it can be used as the base in conventional reactions.Examples of preferred bases include inorganic bases including alkalimetal carbonates such as sodium carbonate, potassium carbonate orlithium carbonate; alkali metal bicarbonates such as sodium bicarbonate,potassium bicarbonate or lithium bicarbonate; alkali metal hydrides suchas lithium hydride, sodium hydride or potassium hydride; alkali metalhydroxides such as sodium hydroxide, potassium hydroxide, bariumhydroxide or lithium hydroxide; and alkali metal fluorides such assodium fluoride or potassium fluoride; alkali metal alkoxides such assodium methoxide, sodium ethoxide, potassium methoxide, potassiumethoxide, potassium t-butoxide or lithium methoxide; organic amines suchas N-methylmorpholine, triethylamine, tripropylamine, tributylamine,diisopropylethylamine, dicyclohexylamine, N-methylpiperidine,4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine,2,6-di(t-butyl)-4-methylpyridine, N,N-dimethylaniline,N,N-diethylaniline, 1,4-diazabicyclo[4.3.0]octane (DABCO),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or1,5-diazabicyclo[4.3.0]nona-5-ene (DBN); or organic metallic bases suchas butyl lithium, lithium diisopropylamide, lithiumbis(trimethylsilyl)amide, and mote preferred examples are alkali metalalkoxides, alkali metal hydrides and organic metallic bases.

[0746] The reaction temperature mainly depends on the starting materialcompounds, the solvent, the phosphonium salt and the base employed inthe reaction. The reaction is usually carried out at a temperature offrom −80° C. to 100° C. and preferably from −20° C. to 50° C.

[0747] The reaction time mainly depends on the starting materialcompounds, the solvent, the phosphonium salt and the base employed inthe reaction. The reaction is usually carried out in a period of from 10minutes to 2 days and preferably from 30 minutes to 12 hours.

[0748] For example, after neutralizing the reaction mixture with dilutedhydrochloric acid and removing, if any, insoluble material(s) byfiltration, the target compound can be obtained by concentrating thereaction mixture or conducting the following steps successively: addingan organic solvent which is not miscible with water (e.g. ethylacetate); separating the organic layer containing the target compound;and then drying over anhydrous sodium sulfate, anhydrous magnesiumsulfate or the like; and removing solvent by evaporation.

[0749] The target compound obtained can be isolated and purified, ifnecessary, by conventional methods such as recrystallization,reprecipitation or chromatography using appropriate eluent(s).

[0750] In step E4, a compound of general formula (XLVIII) is prepared byhydrolyzing a compound (XLVII) in an inert solvent in the presence of abase.

[0751] The solvent used in the above-mentioned reaction is notparticularly limited provided that it has no adverse effect on thereaction and dissolves the starting materials to some extent. Examplesof preferred solvents include alcohols such as methanol or ethanol;aromatic hydrocarbons such as benzene, toluene or xylene; halogenatedhydrocarbons such as methylene chloride, chloroform, carbontetrachloride or dichloroethane; ethers such as diethyl ether,tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; and mixtures of solvents thereof or mixtures of solventsthereof and water. Of these solvents, alcohols and ethers are morepreferred.

[0752] The base used in the above reaction is not particularly limitedprovided that it can be used as the base in conventional reactions.Examples of preferred bases include alkali metal hydroxides such assodium hydroxide, potassium hydroxide, lithium hydroxide or bariumhydroxide.

[0753] The reaction temperature mainly depends on the starting materialcompounds, the solvent and the base employed in the reaction. Thereaction is usually carried out at a temperature of from −20° C. to 200°C. and preferably from 0° C. to 20° C.

[0754] The reaction time mainly depends on the starting materialcompounds, the reaction temperature, the solvent and the base employedin the reaction. The reaction is usually carried out in a period of from30 minutes to 48 hours and preferably from 1 hour to 24 hours. Forexample, after neutralizing the reaction mixture with dilutedhydrochloric acid and removing, if any, insoluble material(s) byfiltration, the target compound can be obtained by concentrating thereaction mixture or conducting the following steps successively: addingorganic solvent which is not miscible with water (e.g. ethyl acetate);separating the organic layer containing the target compound; and thendrying over anhydrous sodium sulfate, anhydrous magnesium sulfate or thelike; and removing solvent by evaporation.

[0755] The target compound obtained can be isolated and purified, ifnecessary, by conventional methods such as recrystallization,reprecipitation or chromatography using appropriate eluent(s).

[0756] Step E5 is a step for preparing a compound of general formula(IL), and in this step, a compound (XLVIII) is converted into thecompound (IL) in an inert solvent in the presence of a base.

[0757] The solvent used in the above-mentioned reaction is notparticularly limited provided that it has no adverse effect on thereaction and dissolves the starting materials to some extent. Examplesof preferred solvents include ethers such as diethyl ether, dioxane,tetrahydrofuran, dimethoxyethane or di(ethylene glycol) dimethyl ether;amides such as N,N-dimethylformamide, N,N-dimethylacetamide,N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorictriamide; or aromatic hydrocarbons such as benzene, toluene or xylene,and more preferred examples are ethers and amides.

[0758] The base used in the above reaction is not particularly limitedprovided that it can be used as the base in conventional reactions.Examples of preferred bases include inorganic bases including alkalimetal hydrides such as lithium hydride, sodium hydride or potassiumhydride; and alkali metal fluorides such as sodium fluoride or potassiumfluoride; alkali metal alkoxides such as sodium methoxide, sodiumethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxideor lithium methoxide; or organic metallic bases such as butyl lithium,lithium diisopropylamide or lithium bis(trimethylsilyl)amide, and morepreferred examples are alkali metal alkoxides and alkali metal hydrides.

[0759] The reaction temperature mainly depends on the starting materialcompounds, the solvent and the base employed in the reaction. Thereaction is usually carried out at a temperature of from −80° C. to 100°C. and preferably from 0° C. to 50° C.

[0760] The reaction time mainly depends on the starting materialcompounds, the reaction temperature, the solvent and the base employedin the reaction. The reaction is usually carried out in a period of from5 minute to 48 hours.

[0761] For example, after neutralizing the reaction mixture with dilutedhydrochloric acid and the like and removing, if any, insolublematerial(s) by filtration, the target compound can be obtained byconcentrating the reaction mixture or conducting the following stepssuccessively: adding an organic solvent which is not miscible with water(e.g. ethyl acetate); separating the organic layer containing

[0762] the target compound; and then drying over anhydrous sodiumsulfate, anhydrous magnesium sulfate or the like; and removing solventby evaporation.

[0763] The target compound obtained can be isolated and purified, ifnecessary, by conventional methods such as recrystallization,reprecipitation or chromatography using appropriate eluent(s).

[0764] Step E6 is a step for preparing a compound (La-1) which is acompound (La) where R¹ is a hydrogen atom and R² and R^(3a) togetherform a group (—(C═O)—). In this step, a compound (IL) is converted intothe target compound (La-1) in an inert solvent in the presence of areducing agent.

[0765] The solvent used in the above-mentioned reaction is notparticularly limited provided that it has no adverse effect on thereaction and dissolves the starting materials to some extent. Examplesof preferred solvents include alcohols such as methanol, ethanol orisopropanol; ethers such as diethyl ether, diisopropyl ether, t-butylmethyl ether, tetralydrofuran or dioxane, aromatic hydrocarbons such asbenzene, toluene or xylene; aliphatic hydrocarbons such as hexane orcyclohexane; or esters such as ethyl acetate or propyl acetate. Of thesesolvents, alcohols are preferred.

[0766] The reducing agent used in the above reaction is not particularlylimited provided that it is usually used in catalytic hydrogenations.Examples of preferred reducing agents include palladium-on-charcoal,platinum oxide, platinum black, rhodium-aluminium oxide,triphenylphosphine-rhodium chloride (Wilkinson complex),palladium-barium sulfate or Raney nickel, and palladium-on-charcoal ismost preferred.

[0767] The pressure in the reduction reaction is not particularlylimited, but the reaction is usually carried out at a pressure of from 1to 10 atmospheric pressures.

[0768] The reaction temperature mainly depends on the starting materialcompounds, the solvent and the base employed in the reaction. Thereaction is usually carried out at a temperature of from 0° C. to 100°C.

[0769] The reaction time mainly depends on the starting materialcompounds, the reaction temperature, the solvent and the base employedin the reaction. The reaction is usually carried out in a period of from5 minutes to 48 hours.

[0770] For example, after removing the catalyst by filtration, thetarget compound can be obtained by concentrating the reaction mixture orconducting the following steps successively: adding an organic solventwhich is

[0771] not miscible with water (e.g. ethyl acetate); separating theorganic layer containing the target compound; and then drying overanhydrous sodium sulfate, anhydrous magnesium sulfate or the like; andremoving solvent by evaporation.

[0772] The target compound obtained can be isolated and purified, ifnecessary, by conventional methods such as recrystallization,reprecipitation or chromatography using appropriate eluent(s).

[0773] In Step E7, a compound (XLVII) is converted into a compound ofgeneral formula (LI) in an inert solvent in the presence of a reducingagent. This step is carried out in a similar manner to that describedearlier in Step E6 of the method E.

[0774] In Step E8, a compound (La-2) which is a compound (La) whereR^(3a) is a hydrogen atom is prepared by hydrolyzing a compound (LI) inan inert solvent in the presence of a base. This step is carried out ina similar manner to that described earlier in Step E4 of the method E.

[0775] Step E9 is a step for preparing a compound (La-1), and in thisstep, a compound (La-2) is converted into the compound (La-1) in aninert solvent in the presence of a base. This step is carried out in asimilar manner to that described earlier in Step E5 of the method E.

[0776] In Step E10, if necessary, a compound (La-3) which is a compound(La) where R² and R^(3a) together do not form a group (—(C═O)—) isprepared by protecting a hydroxyl group of the compound (La-2). Thereaction of this step depends on the nature of the hydroxyl group to beprotected, but it can be carried out by the procedures, for example,described in Protective Groups in Organic Synthesis (third Edition,1999, John Wiley & Sons, Inc.).

[0777] Alternatively, a compound (Lb-3) can be prepared by conductingthe steps E2-E10 of the method E successively using a compound (XLIVb)as the starting material instead of a compound (XLTVa).

[0778] In Method F, a compound (XLVI) is synthesized.

[0779] In the above scheme, Ar and Z are as defined earlier.

[0780] In Step F1, a compound (XLVI) is prepared by the reaction of acompound of general formula (LII) with triphenylphosphine in an inertsolvent.

[0781] The inert solvent used in the above-mentioned reaction is notparticularly limited provided that it has no adverse effect on thereaction. Examples of suitable solvents include aliphatic hydrocarbonssuch as hexane, heptane, ligroin or petroleum ether; aromatichydrocarbons such as toluene, benzene or xylene; halogenatedhydrocarbons such as methylene chloride, chloroform, carbontetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; orethers such as diethyl ether, diisopropyl ether, tetrahydrofuran,dioxane, dimethoxyethane or di(ethylene glycol) dimethyl ether. Of thesesolvents, aromatic hydrocarbons (particularly benzene) are preferred.

[0782] The reaction temperature mainly depends on the starting materialcompounds and the solvent employed in the reaction. The reaction isusually carried out at a temperature of from room temperature to 200°C., preferably from 0° C. to 150° C. and most preferably at 10° C.

[0783] The reaction time mainly depends on the reaction temperature, thestarting material compounds and the solvent employed in the reaction.The reaction is usually carried out in a period of from 5 minutes to 96hours, preferably from 15 minutes to 48 hours and most preferably in 24hours.

[0784] The product thus prepared in each step of the Method F can be, ifnecessary, isolated and purified by conventional techniques such asrecrystallization, reprecipitation or procedures that are usually usedfor the isolation and purification of organic compounds. Examples of thesuitable techniques include adsorption column chromatography using astationary phase such as silica gel, alumina or florisil composed ofmagnesium-silica gel; partition chromatography using a syntheticadsorbent such as Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm &Haas) or Diaion HP-20.(Mitsubishi Chemical Company); ion-exchangechromatography; or normal and reversed phase liquid chromatography usingsilica gel or alkylated silica gel (preferably high performance liquidchromatography). The target compound prepared at each step is isolatedand purified by any of these techniques or a suitable combination ofthese techniques using an appropriate solvent(s) as an eluent.

[0785] The separation of the isomers can be, if necessary, carried outby means of any of the separation/purification procedures mentionedabove after the completion of the reaction of each step or at thesuitable stage after the completion of the desired step.

[0786] The compounds such as (XXVIII), (XXXIV), (XLII), (XLIII) and(LII) used as the starting materials are either known compounds or canbe prepared easily by known or similar methods.

[0787] The aminoalcohol derivatives of the general formula (I) of thepresent invention, pharmacologically acceptable salts, esters or otherderivatives thereof exhibit an excellent immunosuppressive effect withlow toxicity. Further, pharmaceutical compositions containing thecompound having the general formula (I) of the present invention or apharmacologically acceptable salt, ester or other derivative thereof asthe active ingredient are useful as preventives and/or therapeuticagents for, particularly, autoimmune diseases such as systemic lupuserythematosus, rheumatoid arthritis, polymyositis, dermatomyositis,scleoderma, Behcet's disease, Chron disease, ulcerative colitis,autoimmune hepatitis, aplastic anemia, idiopathic thrombocytopenicpurpura, autoimmune hemolytic anemia, multiple sclerosis, autoimmunebullosis, vulgarity psoriasis, vasculitis syndrome, Wegener's granuloma,uveitis, cryptogenic fibrosing alveolitis, Goodpasture's syndrome,sarcoidosis, allergic granulomatous angitis, bronchial asthma,myocarditis, cardiomyopathy, aortic arch syndrome, myocardialpostinfarction syndrome, primary pulmonary hypertension, minimal changenephrotic syndrome, membranous nephropathy, membranoproliferativeglomerulonephritis, focal glomerular sclerosis, crescentglomerulonephritis, myasthenia gravis, inflammatory neuropathy, atopicdermatitis, chronic actinic dermatitis, acute polyarthritis, Sydenhanchorea disease, progressive systemic sclerosis, adult onset typediabetes mellitus, insulin dependent diabetes mellitus, juvenilediabetes, atherosclerosis, glomerular nephritis, tuburointerstitialnephritis, primary biliary cirrhosis, primary sclerosing cholangitis,fulminant hepatic failure, viral hepatitis, GVHD, immunologicalrejection following organ transplantation, contact dermatitis, sepsis,or other immunology related diseases.

[0788] In addition, the novel optically active aminoalcohol compoundssuch as (La) and (Lb) of the present invention are useful asintermediates for the manufacturing of the medicaments.

[0789] On the other hand, optically active2-substituted-2-amino-1,3-propanediol monoester derivatives (XLIVa) and(XLIVb) are preferred synthetic intermediates in the production of theoptically active aminoalcohol compounds (La) and (Lb) mentioned aboveand can be prepared easily and conveniently in a good yield by acylatingselectively only one of the hydroxyl groups of the2-substituted-2-amino-1,3-propanediol derivative (XLII) used as thestarting material with a vinyl carboxylate derivative (XLIII) in thepresence of lipase.

[0790] The compounds of general formula (I) of the present invention andpharrnacologically acceptable salts or esters thereof can beadministered for treatment or prevention of the above-mentioned diseasesas a suitable dosage form, which is prepared from the compound alone orby mixing with a suitable pharmacologically acceptable excipient and/ordiluent, such as tablets, capsules, granules, powders or syrups for oraladministration, or injections or suppositories for parenteraladministration.

[0791] Such formulations may be prepared, according to well knowntechniques, using additives such as excipients, lubricants, binders,disintegrators, stabilizers, corrigents and/or diluents. Examples ofsuitable excipients include organic excipients including glucosederivatives such as lactose, sucrose, glucose, mannitol and sorbitol;starch derivatives such as corn starch, potato starch, α-starch anddextrin; cellulose derivatives such as crystalline cellulose; gumArabic; dextran; and Pullulan, and inorganic excipients includingsilicate derivatives such as anhydrous light silicic acid, syntheticaluminium silicate, calcium silicate and magnesium metaaluminosilicate;phosphates such as calcium hydrogen phosphate; carbonates such ascalcium carbonate; and sulfates such as calcium sulfate. Examples ofsuitable lubricants include stearic acid; metal stearates such ascalcium stearate and magnesium stearate; talc; colloidal silica; waxessuch as bee gum or spermaceti; boric acid; adipic acid; sulfates such assodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine;sodium salt of fatty acid; lauryl sulfates such as lauryl sodium sulfateor lauryl magnesium sulfate; silicates such as anhydrous silicic acid orsilicic hydrate; and the above-mentioned starch derivatives. Examples ofsuitable binders include hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, Macrogol and the compoundsdescribed above as an excipient. Examples of suitable disintegratorsinclude cellulose derivatives such as low substitutedhydroxypropylcellulose, carboxymethyl cellulose, calcium carboxymethylcellulose, internal-crosslinked sodium carboxymethyl cellulose;chemically modified starch-cellulose derivatives such as carboxymethylstarch, sodium carboxymethyl starch or cross-linkedpolyvinylpyrrolidone. Examples of suitable stabilizers includep-hydroxybenzoic esters such as methylparaben or propylparaben; alcoholssuch as chlorobutanol, benzyl alcohol or phenylethyl alcohol;benzalkonium chloride; phenols such as phenol or cresol; thimerosal;dehydroacetic acid; and sorbic acid. Corrigents include sweeteners,souring agents and flavors that are commonly used in the art.

[0792] The dosage may vary depending on a variety of factors such as thesymptoms and age of the patient and route of administration. A suitabledosage level for oral administration is from 0.05 mg (preferably 5 mg)per day as a lower limit to 200 mg (preferably 40 mg) per day as anupper limit for adults (e.g. human adults). On the other hand, asuitable dosage level for intravenous administration is from 0.01 mg(preferably 1 mg) per day as a lower limit to 100 mg (preferably 10 mg)per day as an upper limit for adults. The dosage can be administeredeither as a single unit dosage or, if necessary, the dosage may bedivided into convenient sub-units and administered from one to six timesthroughout the day depending on the symptoms of the patient (e.g. humanpatient).

[0793] The present invention is further dscribed by Examples and Testexamples, however this invention is not limited to these Examples andTest examples.

EXAMPLE 1(2R)-Amino-2-methyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol(exemplification compound No.1-770) EXAMPLE 1(a)2-Methyl-2-(2-thienyl)ethylmalonic acid diethylester

[0794] Sodium hydride (55%, 18.8 g, 0.43 mol) was suspended indimethylformamide (200 ml), and methylmalonic acid diethylester (50.0 g,0.29 mol) was slowly added thereto for 30 minutes in an ice bath, andthen the reaction solution was stirred for 30 minutes. To the reactionsolution was added 2-(2-iodoethyl)thiophene (75.2 g, 0.32 mol) dissolvedin dimethylformamide (200 ml) under-a nitrogen atmosphere for 15minutes, and then the reaction mixture was stirred for 4 hours at roomtemperature. The reaction mixture was poured into ice-cold 10%hydrochloric acid (500 ml), and extracted with ethyl acetate. Theorganic layer was washed with a saturated aqueous sodium chloridesolution, and dried over anhydrous magnesium sulfate. The solvent wasconcentrated under reduced pressure, and the residue was purified byflash chromatography on a silica gel column (elution solvent;hexane:ethyl acetate=10:1-5:1) to afford the title compound (53.1 g, 65%yield) as a colorless oil.

[0795] Infrared absorption spectrum ν_(max) cm⁻¹ (CHCl₃): 2986, 1726,1271, 1252 Mass spectrum (FAB) m/z: 285 (((M+H)⁺)

EXAMPLE 1(b) 2-Methyl-2-(2-thienyl)ethylmalonic acid monoethylester

[0796] 2-Methyl-2-(2-thienyl)ethylmalonic acid diethylester (52.7 g,0.19 mol) obtained in Example 1(a) was dissolved in a mixture of ethanol(240 ml) and water (80 ml), potassium hydroxide (11.4 g, 0.20 mol) wasadded thereto in an ice bath, and the solution was stirred for 2 hours.And then potassium hydroxide (5.7 g, 0.1 mol) was added thereto threetimes, one portion every I hour, and the reaction solution was stirredfor 6 hours in total. Water (300 ml) and ice-cold 10% hydrochloric acid(500 ml) were added to the reaction solution, and the solution wasextracted with ethyl acetate. The organic layer was washed with asaturated aqueous sodium chloride solution, and dried over anhydrousmagnesium sulfate. The solvent was concentrated in vacuo, and theresidue was purified by flash chromatography on a silica gel column(elution solvent; hexane:ethyl acetate=2:1−0:1) to afford the titlecompound (28.6 g, 60% yield) as a pale yellow oil.

[0797] Infrared absorption spectrum ν_(max) cm⁻¹ (CHCl₃): 2987, 1732,1712, 1251, 1109 Mass spectrum (FAB) m/z: 257 ((M+H)⁺)

EXAMPLE 1(c) 2-Methoxycarbonylamino-2-methyl-4-(2-thienyl)butanoic acidethylester

[0798] 2-Methyl-2-(2-thienyl)ethylmalonic acid monoethylester (19.0 g,74.3 mmol) obtained in Example 1(b) was dissolved in benzene (450 ml),and triethylamine (11.4 ml, 81.7 mmol) and diphenylphosphoric acid azide(17.6 ml, 81.7 mmol) were added thereto, and after stirring for 10minutes at room temperature, the reaction solution was stirred foranother 1.5 hours at 80° C. Subsequently, methanol (60.3 ml, 1.49 mol)was slowly added dropwise thereto for 30 minutes at 80° C. followed bystirring for 8 hours. The reaction mixture was poured into water (500ml) and extracted with ethyl acetate. The organic layer was washed witha saturated aqueous sodium chloride solution, and dried over anhydrousmagnesium sulfate. The solvent was concentrated in vacuo, and theresidue was purified by flash chromatography on a silica gel column(elution solvent; hexane:ethyl acetate=8:1−4:1) to afford the titlecompound (14.7 g, 69% yield) as a colorless oil.

[0799] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 7.11(1H, d, J=5.1 Hz), 6.90 (1H, dd, J=5.1, 3.5 Hz), 6.77 (1H, d, J=3.5 Hz),5.69 (1H, brs), 4.19 (2H, q. J=7.3 Hz), 3.66 (3H, s), 2.84 (2H, dd,J=10.5, 10.5 Hz), 2.64 (2H, m), 2.20 (2H, dd, J=10.5, 8.4 Hz), 1.61 (3H,s), 1.28 (3H, t, J=7.3 Hz) Infrared absorption spectrum ν_(max) cm⁻¹(CHCl₃): 3417, 2987, 1719, 1503, 1453, 1081 Mass spectrum (FAB) m/z: 286((M+H)⁺)

EXAMPLE 1(d) 2-Methoxycarbonylamino-2-methyl-4-(2-thienyl)butan-1-ol

[0800] 2-Methoxycarbonylamino-2-methyl-4-(2-thienyl)butanoic acidethylester (14.7 g, 51.6 mmol) obtained in Example 1(c) was dissolved ina mixture of ethanol (150 ml) and tetrahydrofuran (100 ml), and thensodium borohydride (5.07 g, 0.13 mol) and lithium chloride (5.68 g, 0.13mol) were added thereto followed by stirring overnight at roomtemperature under a nitrogen atmosphere. And next morning, sodiumborohydride (5.07 g, 0.13 mol) and lithium chloride (5.68 g, 0.13 mol)were added thereto in a similar way, and the reaction mixture wasstirred once more overnight at room temperature under a nitrogenatmosphere. Similar procedures described above were carried out for moretwo days. The reaction mixture was poured into ice-cold 10% hydrochloricacid (500 ml), and the resulting solution was extracted with ethylacetate. The organic layer was washed with a saturated aqueous sodiumchloride solution, and dried over anhydrous magnesium sulfate. Thesolvent was concentrated in vacuo, and the residue was purified by flashchromatography on a silica gel column (elution solvent; hexane:ethylacetate=2:1−1:5) to afford the title compound (11.7 g, 93% yield) as awhite crystalline solid.

[0801] Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3406, 3244,1687, 1562, 1264, 1089 Mass spectrum (FAB) m/z: 244 ((M+H)⁺) Anal.Calcd.(%) for C₁₁H₁₇NO₃S: C, 54.30; H, 7.04; N, 5.76; S, 13.18 Found: C,54.18; H, 6.98; N, 5.78; S, 13.34

EXAMPLE 1(e)2-Methoxycarbonylamino-2-methyl-4-(5-bromothiophen-2-yl)butan-1-ol

[0802] 2-Methoxycarbonylamino-2-methyl-4-(2-thienyl)butan-1-ol (11.7 g,48.0 mmol) obtained in Example 1(d) was dissolved in dimethylformamide(120 ml), and N-bromosuccinimide (10.8 g, 60.8 mmol) was added theretoin an ice bath followed by stirring for 4 hours at room temperatureunder a nitrogen atmosphere. The reaction mixture was poured intoice-cold 10% hydrochloric acid (300 ml), and extracted with ethylacetate. The organic layer was washed with a saturated aqueous sodiumchloride solution, and dried over anhydrous magnesium sulfate. Thesolvent was concentrated in vacuo, and the residue was purified by flashchromatography on a silica gel column (elution solvent; hexane:ethylacetate=4:1−1:3) to afford the title compound (12.4 g, 80% yield) as apale yellow oil.

[0803] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 6.84(1H, d, J=3.7 Hz), 6.57 (1H, d, J=3.7 Hz), 4.80 (1H, brs), 3.68 (2H, m),3.64 (3H, s), 2.80 (2H, m), 1.9-2.2 (2H, m), 1.24 (3H, s) Infraredabsorption spectrum ν_(max) cm⁻¹ (CHCl₃): 3627, 3436, 2956, 1722, 1711,1513, 1259, 1087, 1048 Mass spectrum (FAB) m/z: 322 ((M+H)⁺)

EXAMPLE 1(f) 4-[2-(5-Bromothiophen-2-yl)]ethyl-4-methyloxazolidin-2-one

[0804]2-Methoxycarbonylamino-2-methyl-4-(5-bromothiophen-2-yl)butan-1-ol (12.4g, 38.6 mmol) obtained in Example 1(e) was dissolved indimethylformamide (125 ml), and potassium t-butoxide (6.50 g, 57.9 mmol)was added thereto in an ice bath under a nitrogen atmosphere followed bystirring for 3 hours at the same temperature. The reaction mixture waspoured into ice-cold 10% hydrochloric acid (300 ml), and extracted withethyl acetate. The organic layer was washed with a saturated aqueoussodium chloride solution, and dried over anhydrous magnesium sulfate.The solvent was concentrated in vacuo, and the residue was purified byflash chromatography on a silica gel column (elution solvent;hexane:ethyl acetate=4:1−1:2) to afford the title compound (10.7 g, 95%yield) as a white crystalline solid.

[0805] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 6.86(1H, d, J=3.7 Hz), 6.58 (1H, d, J=3.7 Hz), 5.73 (1H, brs), 4.18 (1H, d,J=8.6 Hz), 4.08 (1H, d, J=8.6 Hz), 2.84 (2H, m), 1.94 (2H, m), 1.41 (3H,s) Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3211, 1749, 1399,1037, 798 Mass spectrum (FAB) m/z: 290 ((M+H)⁺) Anal. Calcd.(%) forC₁₀H₁₂NO₂SBr: C, 41.39; H, 4.17; N, 4.83; S, 11.05; Br, 27.54 Found: C,41.36; H, 4.04; N, 4.82; S, 11.08; Br, 27.29

EXAMPLE 1(g)(4R)-[2-(5-Bromothiophen-2-yl)]ethyl-4-methyloxazolidin-2-one and(4S)-[2-(5-Bromothiophen-2-yl)]ethyl-4-methyloxazolidin-2-one

[0806] 4-[2-(5-Bromothiophen-2-yl)]ethyl-4-methyloxazolidin-2-oneobtained in Example 1(f) was subjected to chromatographic opticalresolution using preparative HPLC with a chiral stationary phase column(ChiralCel OD, Daicel Chemical Industries, LTD.), (column, ChiralCel OD(2 cmφ×25 cm); elution solvent, hexane:2-propanol=70:30; flow rate, 5ml/min). The former compound, which was eluted at 55 minutes, was the4S-form, and the latter compound eluted at 77 minutes was the 4R-form.Their absolute configurations were determined by X-ray crystal structureanalysis.

[0807] (4S) Form; [α]_(D) ²⁴−4.2 (c 1.03, methanol) (4R) Form; [α]_(D)²⁴+4.2 (c 1.00, methanol)

EXAMPLE 1(h)(4R)-{2-[5-(5-Cyclohexylpent-1-ynyl)thiophen-2-yl]}ethyl-4-methyloxazolidin-2-one

[0808] (4R)-[2-(5-Bromothiophen-2-yl)]ethyl-4-methyloxazolidin-2-one(450 mg, 1.55 mmol) obtained in Example 1(g) was dissolved indimethylformamide (4.5 ml), and 5-cyclohexylpent-1-yne (50% xylenesolution) (1.4 g, 4.65 mmol), triethylamine (2.16 ml, 15.5 mmol), copper(I) iodide (30 mg, 0.16 mmol) anddichlorobis(triphenylphosphine)palladium (109 mg, 0.16 mmol) were addedthereto, and then the reaction mixture was stirred for 2 hours at 80° C.under a nitrogen atmosphere. The reaction solution was poured intowater, extracted with ethyl acetate, and the ethyl acetate layer waswashed with a saturated aqueous sodium chloride solution. After theethyl acetate layer was dried over anhydrous sodium sulfate, the solventwas concentrated in vacuo, and the residue was purified bychromatography on a silica gel column (elution solvent; hexane:ethylacetate=4:1−3:2) to afford the title compound (56 mg, 82% yield).

[0809] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 6.92(1H, d, J=3.6 Hz), 6.63 (1H, d, J=3.6 Hz), 5.45 (1H, brs), 4.18 (1H, d,J=8.6 Hz), 4.07 (1H, d, J=8.6 Hz), 2.78-2.90 (2H, m), 2.38 (2H, t, J=7.2Hz), 1.92-2.00 (2H, m), 1.55-1.75 (7H, m), 1.40 (3H, s), 1.10-1.35 (6H,m), 0.83-0.95 (2H, m) Infrared absorption spectrum ν_(max) cm⁻¹ (KBr):3450, 2926, 2852, 1758, 1382, 1046

EXAMPLE 1(i)(2R)-Amino-2-methyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol

[0810](4R)-{2-[5-(5-Cyclohexylpent-1-ynyl)thiophen-2-yl]}ethyl-4-methyloxazolidin-2-one(456 mg, 1.27 mmol) obtained in Example 1(h) was dissolved in a mixtureof tetrahydrofuran (1 ml) and methanol (2 ml), and a 5 N aqueouspotassium hydroxide solution (2 ml) was added thereto in an ice bathfollowed by heating under reflux for 18 hours. Water was added to thereaction solution, and the resulting mixture was extracted withdichloromethane. After the layer of dichloromethane was dried overanhydrous sodium sulfate, the solvent was concentrated in vacuo, and theresidue was purified by chromatography on a silica gel column (elutionsolvent; dichloromethane:methanol=20:1-dichloromethane:methanol:aqueousammonia=10:1:0.1) to afford the title compound (353 mg, 83% yield).

[0811] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 6.92(1H, d, J=3.5 Hz), 6.62 (1H, d, J=3.5 Hz), 3.37 (1H, d, J=10.5 Hz), 3.32(1H, d, J=10.5 Hz), 2.75-2.90 (2H, m), 2.38 (2H, t, J=7.1 Hz), 1.52-1.79(9H, m), 1.12-1.33 (6H, m), 1.11 (3H, s), 0.81-0.96 (2H, m) Infraredabsorption spectrum ν_(max) cm⁻¹ (CHCl₃): 2925, 2852, 1449, 1041 Massspectrum (FAB) m/z: 334 ((M+H)⁺) Anal. Calcd.(%) for C₂₀H₃₁NOS.0.3H₂O:C, 70.87; H, 9.40; N, 4.13; S, 9.46 Found: C, 70.83; H, 9.21; N, 4.22;S, 9.64 [α]_(D) ²⁴−2.0 (c 0.60, methanol)

EXAMPLE 2(2R)-Amino-2-methyl-4-[5-(6-cyclohexylhex-1-ynyl)thiophen-2-yl]butan-1-ol(exemplification compound No. 1-882)

[0812] The title compound was obtained according to a similar reactionto that described in Example 1.

[0813] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 6.91(1H, d, J=3.6 Hz), 6.62 (1H, d, J=3.6 Hz), 3.39 (1H, d, J=10.7 Hz), 3.34(1H, d, J=10.7 Hz), 2.82 (2t, J=8.5 Hz), 2.40 (2H, t, J=6.9 Hz),2.18-1.92 (4H, m), 1.88-1.51 (8H, m), 1.47-1.38 (2H, m), 1.28-1.07 (9H,m), 0.93-0.78 (2H, m) Infrared absorption spectrum ν_(max) cm⁻¹ (KBr):3327, 3275, 2922, 2850, 1611, 1563, 1539, 1447, 1065, 1040, 803, 521

EXAMPLE 32-Amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol(exemplification compound No. 1-824)

[0814] The title compound was obtained according to a similar reactionto that described in Example 1 using a racemic mixture of4-[2-(5-bromothiophen-2-yl)]ethyl-4-methyloxazolidin-2-one as a startingmaterial.

[0815] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:7.32-7.26 (2H, m), 7.25-7.16 (3H, m), 6.94 (1H, d, J=3.6 Hz), 6.93 (1H,d, J=3.6 Hz), 3.37 (1H, d, J=10.8 Hz), 3.31 (1H, d, J=10.4 Hz), 2.83(2H, t, J=8.4 Hz), 2.77 (2H, t J=7.6 Hz), 2.42 (2H, t, J=7.2 Hz),1.96-1.85 (2H, m), 1.84-1.64(2H, m), 1.50 (3H, brs), 1.11 (3H, s)Infrared absorption spectrum ν_(max) cm⁻¹ (liquid film): 2931, 2859,1748, 1602, 1584, 1538, 1496, 1455, 1191, 1053, 908, 804, 747, 700, 573

EXAMPLE 42-Amino-2-methyl-4-{5-[5-(4-methoxyphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-olhydrochloride (exemplification compound No.1-849)

[0816] The title compound was obtained according to a similar reactionto that described in Example 1 using a racemic mixture of4-[2-(5-bromothiophen-2-yl)]ethyl-4-methyloxazolidin-2-one as a startingmaterial.

[0817] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 8.07(3H, brs), 7.10 (2H, d, J=8.6 Hz), 6.89 (1H, d, J=3.5 Hz), 6.81 (2H, d,J=8.6 Hz), 6.65 (1H, d, J=3.5 Hz), 4.72 (1H, brs), 3.77 (3H, s), 3.65(2H, s), 2.78-2.97 (2H, m), 2.66 (2H, t, J=7.5 Hz), 2.36 (2H, t, J=7.1Hz), 1.77-2.20 (4H, m), 1.36 (3H, s) Infrared absorption spectrumν_(max) cm⁻¹ (KBr): 3370, 3009, 2932, 1589, 1511, 1245, 1070, 1036

EXAMPLE 52-Amino-2-methyl-4-{5-[5-(4-fluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-olmaleate (exemplification compound No. 1-833)

[0818] The title compound was obtained according to a similar reactionto that described in Example 1 using a racemic mixture of4-[2-(5-bromothiophen-2-yl)]ethyl-4-methyloxazolidin-2-one as a startingmaterial.

[0819] Nuclear magnetic resonance spectrum (400 MHz, CD₃OD) δ ppm:7.18-7.25 (2H, m), 6.95-7.03 (2H, m), 6.94 (1H, d, J=3.6 Hz), 6.73 (1H,d, J=3.6 Hz), 6.25 (2H, s), 3.61 (1H, d, J=11.6 Hz), 3.52 (1H, d, J=11.6Hz), 2.80-2.95 (2H, m), 2.74 (2H, t, J=7.6 Hz), 2.40 (2H, t, J=7.0 Hz),1.80-2.10 (4H, m), 1.31 (3H, s) Infrared absorption spectrum ν_(max)cm⁻¹ (KBr): 3352, 2940, 1578, 1509, 1385, 1367, 1221, 1194

EXAMPLE 62-Amino-2-methyl-4-[5-(biphenyl-4-yl)ethynylthiophen-2-yl]butan-1-ol(exemplification compound No. 1-742)

[0820] The title compound was obtained according to a similar reactionto that described in Example 1 using a racemic mixture of4-[2-(5-bromothiophen-2-yl)]ethyl-4-methyloxazolidin-2-one as a startingmaterial.

[0821] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:7.55-7.65 (6H, m), 7.43-7.50 (2H, m), 7.33-7.40 (1H, m), 7.11 (1H, d,J=3.6 Hz), 6.72 (1H, d, J=3.6 Hz), 3.39 (1H, d, J=10.4 Hz), 3.34 (1H, d,J=10.4 Hz), 2.80-2.95 (2H, m), 1.70-1.90 (2H, m), 1.13 (3H, s) Infraredabsorption spectrum ν_(max) cm⁻¹ (KBr): 3335, 3075, 2924, 1485, 1463,1051, 837, 809, 764, 698

EXAMPLE 72-Amino-2-methyl-4-[5-(4-butylphenyl)ethynylthiophen-2-yl]butan-1-ol(exemplification compound No. 1-737)

[0822] The title compound was obtained according to a similar reactionto that described in Example 1 using a racemic mixture of4-[2-(5-bromothiophen-2-yl)]ethyl-4-methyloxazolidin-2-one as a startingmaterial.

[0823] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 7.42(2H, d, J=8.1 Hz), 7.36-7.15 (5H, m), 7.16 (2H, d, J=8.1 Hz), 7.07 (1H,d, J=3.3 Hz), 6.70 (1H, d, J=3.3 Hz), 3.99 (2H, s), 3.36-3.24 (2H, m),2.92-2.81 (2H, m), 2.01-1.95 (2H, m), 2.65-2.26 (3H, m), 1.11 (3H, s)Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3326, 3264, 2926, 2904,1603, 1541, 1485, 1468, 1454, 1211, 1063, 1033, 803, 701

EXAMPLE 82-Amino-2-methyl-4-[5-(4-cyclohexylphenyl)ethynylthiophen-2-yl]butan-1-ol(exemplification compound No.1-741)

[0824] The title compound was obtained according to a similar reactionto that described in Example 1 using a racemic mixture of4-[2-(5-bromothiophen-2-yl)]ethyl-4-methyloxazolidin-2-one as a startingmaterial.

[0825] Nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:7.42 (2H, d, J=8.2 Hz), 7.26 (2H, d, J=8.2 Hz), 7.20 (1H, d, J=3.6 Hz),6.83 (1H, d, J=3.6 Hz), 3.56-3.24 (5H, m), 2.88-2.70 (2H, m), 1.89-1.52(7H, m), 1.43-1.21 (6H, m), 0.97 (3H, s) Infrared absorption spectrumν_(max) cm⁻¹ (KBr): 3326, 3279, 2924, 2850, 1645, 1567, 1539, 1448,1385, 1055, 826, 547

EXAMPLE 92-Amino-2-methyl-4-[5-(4-propylphenyl)ethynylthiophen-2-yl]butan-1-ol(exemplification compound No. 1-736)

[0826] The title compound was obtained according to a similar reactionto that described in Example 1 using a racemic mixture of4-[2-(5-bromothiophen-2-yl)]ethyl-4-methyloxazolidin-2-one as a startingmaterial.

[0827] Nuclear magnetic resonance spectrum (400 MHz, CD₃OD) δ ppm: 7.36(2H, d, J=8.2 Hz), 7.18(2H, d, J=8.2 Hz), 7.06 (1H, d, J=3.5 Hz), 6.76(1H, d, J=3.5 Hz), 3.39 (1H, d, J=10.7 Hz), 3.38 (1H, d, J=10.7 Hz),2.93-2.80 (2H, m), 2.69-2.58 (2H, m), 1.83-1.59 (4H, m), 1.10 (3H, s),0.94 (3H, t, J=7.3 Hz) Infrared absorption spectrum ν_(max) cm⁻¹ (KBr):3323, 3267, 2959, 2929, 2869, 1611, 1540, 1510, 1468, 1213, 1066, 1035,816, 804, 510

EXAMPLE 102-Amino-2-methyl-4-[5-(4-propyloxyphenyl)ethynylthiophen-2-yl]butan-1-ol(exemplification compound No.1-740)

[0828] The title compound was obtained according to a similar reactionto that described in Example 1 using a racemic mixture of4-[2-(5-bromothiophen-2-yl)]ethyl-4-methyloxazolidin-2-one as a startingmaterial.

[0829] Nuclear magnetic resonance spectrum (400 MHz, CD₃OD) δ ppm: 7.37(2H, d, J=8.9 Hz), 7.03 (1H, d, J=3.6 Hz), 6.89 (2H, d, J=8.9 Hz), 6.75(1H, d, J=3.6 Hz), 3.95 (2H, t, J=6.3 Hz), 3.39 (1H, d, J=10.7 Hz), 3.35(1H, d, J=10.7 Hz), 2.92-2.78 (2H, m), 1.86-1.72 (4H, m), 1.09 (3H, s),1.04 (3H, t, J=7.6 Hz) Infrared absorption spectrum ν_(max) cm⁻¹ (KBr):3329, 3275, 2964, 2936, 1604, 1509, 1466, 1249, 1065, 975, 832, 807

EXAMPLE 11(2R)-Amino-2-methyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol(exemplification compound No.1-98)

[0830](2R)-Amino-2-methyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol(175 mg, 0.53 mmol) obtained in Example 1 was dissolved in ethanol (9ml), and 10% palladium-charcoal (90 mg) was added thereto, and then themixture was stirred under a hydrogen atmosphere for 2 hours. After thepalladium-charcoal was filtered out through Celite, the filtrate wasevaporated to dryness under reduced pressure to give the title compound(150 mg, 85% yield).

[0831] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 6.58(1H, d, J=3.2 Hz), 6.55 (1H, d, J=3.2 Hz), 3.36 (1H, d, J=10.5 Hz), 3.31(1H, d, J=10.5 Hz), 2.75-2.90 (2H, m), 2.73 (2H, t, J=7.6 Hz), 1.59-1.83(9H, m), 1.12-1.32 (10H, m), 1.11(3H, s), 0.81-0.89 (2H, m) Infraredabsorption spectrum ν_(max) cm⁻¹ (CHCl₃): 2926, 2853, 1440, 1042 Massspectrum (FAB) m/z: 338 ((M+H)⁺) Anal. Calcd.(%) for C₂₀H₃₅NOS.H₂O: C,67.56; H, 10.49; N, 3.94; S, 9.01 Found: C, 67.11; H, 10.03; N, 3.93; S,8.88 [α]_(D) ²⁴−0.7 (c 3.03, methanol)

EXAMPLE 12(2R)-Amino-2-methyl-4-[5-(6-cyclohexylhexyl)thiophen-2-yl]butan-1-ol(exemplification compound No. 1-210)

[0832] The title compound was obtained according to a similar reactionto that described in Example 11 using(2R)-Amino-2-methyl-4-[5-(6-cyclohexylhex-1-ynyl)thiophen-2-yl]butan-1-olobtained in Example 2.

[0833] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 6.58(1H, d, J=3.3 Hz), 6.55 (1H, d, J=3.3 Hz), 3.37 (1H, d, J=10.4 Hz), 3.32(1H, d, J=10.4 Hz), 2.68-2.93 (4H, m), 1.05-1.85 (24H, m), 0.77-0.93(2H, m) Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3334, 3269,3159, 2922, 2850, 1465, 1448, 1060 Mass spectrum (EI) m/z: 351 (M⁺)Anal. Calcd.(%) for C₂₁H₃₇NOS: C, 71.74; H, 10.61; N, 3.98; S, 9.12Found: C, 71.47; H, 10.48; N, 3.98; S, 9.37 [α]^(D) ²⁴−1.3 (c 1.15,methanol)

EXAMPLE 132-Amino-2-methyl-4-[5-(5-phenylpentyl)thiophen-2-yl]butan-1-ol(exemplification compound No.1-152)

[0834] The title compound was obtained according to a similar reactionto that described in Example 11 using2-amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-olobtained in Example 3.

[0835] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:7.31-7.24 (2H, m), 7.20-7.14 (3H, m), 6.58 (1H, d, J=2.8 Hz), 6.54 (1H,d, J=3.6 Hz), 3.36 (1H, d, J=10.8 Hz), 3.31 (1H, d, J=10.4 Hz), 2.81(2H, t, J=8.4 Hz), 2.74 (2H, t, J=7.6 Hz), 2.61 (2H, t, J=7.6 Hz),1.84-1.56 (6H, m), 1.52(3H, brs), 1.46-1.37 (2H, m), 1.11(3H, s)Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3333, 3263, 2927, 2852,1496, 1453, 1059, 969, 928, 798, 747, 699, 569

EXAMPLE 142-Amino-2-methyl-4-{5-[5-(4-methoxyphenyl)pentyl]thiophen-2-yl}butan-1-ol(exemplification compound No.1-177)

[0836] The title compound was obtained according to a similar reactionto that described in Example 11 using2-amino-2-methyl-4-{5-[5-(4-methoxyphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-olobtained in Example 4.

[0837] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 7.08(2H, d, J=8.5 Hz), 6.82 (2H, d, J=8.5 Hz), 6.58 (1H, d, J=3.3 Hz), 6.54(1H, d, J=3.3 Hz), 3.79 (3H, s) 3.36 (1H, d, J=10.5 Hz), 3.31 (1H, d,J=10.5 Hz), 2.70-2.85 (4H, m), 2.55 (2H, t, J=7.7 Hz), 1.55-1.85 (6H,m), 1.35-1.45 (2H, m), 1.11 (3H, s) Infrared absorption spectrum ν_(max)cm⁻¹ (KBr): 3333, 3263, 2926, 2852, 1514, 1247, 1061, 1029

EXAMPLE 152-Amino-2-methyl-4-{5-[5-(4-fluorophenyl)pentyl]thiophen-2-yl}butan-1-ol(exemplification compound No. 1-161)

[0838] The title compound was obtained according to a similar reactionto that described in Example 11 using2-amino-2-methyl-4-{5-[5-(4-fluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-olobtained in Example 5.

[0839] Nuclear magnetic resonance spectrum (400 MHz, CD₃OD) δ ppm:7.12-7.18 (2H, m), 6.92-6.98 (2H, m), 6.63 (1H, d, J=3.5 Hz), 6.56 (1H,d, J=3.5 Hz), 6.25 (2H, s), 3.61 (1H, d, J=11.6 Hz), 3.51 (1H, d, J=11.6Hz), 2.70-2.90 (4H, m), 2.58 (2H, t, J=7.6 Hz), 1.88-2.03 (2H, m),1.57-1.70 (4H, m), 1.28-1.42 (5H, m) Infrared absorption spectrumν_(max) cm⁻¹ (KBr): 2929, 2854, 1578, 1509, 1464, 1387, 1356, 1223

EXAMPLE 162-Amino-2-methyl-4-{5-[2-(biphenyl-4-yl)ethyl]thiophen-2-yl}butan-1-ol(exemplification compound No. 1-44)

[0840] The title compound was obtained according to a similar reactionto that described-in Example 11 using2-amino-2-methyl-4-[5-(biphenyl-4-yl)ethynylthiophen-2-yl]butan-1-olobtained in Example 6.

[0841] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:7.25-7.65 (9H, m), 6.60 (1H, d, J=3.5 Hz), 6.59 (1H, d, J=3.5 Hz), 3.37(1H, d, J=10.5 Hz), 3.32 (1H, d, J=10.5 Hz), 3.06-3.15 (2H, m),2.95-3.04 (2H, m), 2.75-2.90 (2H, m), 1.65-1.85 (2H, m), 1.12 (3H, s)Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3333, 3265, 2924, 2852,1598, 1486, 1448, 1059, 798, 695

EXAMPLE 17(2R)-Amino-2-methyl-4-[5-(5-cyclohexylpentanoyl)thiophen-2-yl]butan-1-ol(exemplification compound No.1-1331)

[0842](2R)-Amino-2-methyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol(126 mg, 0.41 mmol) obtained in Example 1 was dissolved in methanol (2ml), and 6N sulfuric acid (2 ml) was added thereto followed by heatingunder reflux for 4 hours. After the reaction solution was made alkalinewith a 1N aqueous sodium hydroxide solution, the resulting solution wasextracted with dichloromethane. The dichloromethane layer was dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure to give the title compound (130 mg, 91% yield).

[0843] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 7.54(1H, d, J=3.7 Hz), 6.84 (1H, d, J=3.7 Hz), 3.39 (1H, d, J=10.4 Hz), 3.34(1H, d, J=10.4 Hz), 2.78-2.98 (4H, m), 1.13 (3H, brs), 0.8-1.9 (19H, m)Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3332, 3267, 3134, 2922,2851, 1647, 1457, 1057 Mass spectrum (EI) mz: 351 (M⁺) Anal. Calcd.(%)for C₂₀H₃₃NO₂S: C, 68.33; H, 9:46; N, 3.98; S, 9.12 Found: C, 67.99; H,9.48; N, 3.92; S, 9.11 [α]_(D) ²⁴−2.1 (c 1.03, methanol)

EXAMPLE 18(2R)-Amino-2-methyl-4-[5-(6-cyclohexylhexanoyl)thiophen-2-yl]butan-1-ol(exemplification compound No.1-1357)

[0844] The title compound was obtained according to a similar reactionto that described in Example 17 using(2R)-amino-2-methyl-4-[5-(6-cyclohexylhex-1-ynyl)thiophen-2-yl]butan-1-olobtained in Example 2.

[0845] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 7.53(1H, d, J=3.9 Hz), 6.63 (1H, d, J=3.9 Hz), 3.39 (1H, d, J=10.5 Hz), 3.34(1H, d, J=10.5 Hz), 2.80-2.95 (4H, m), 1.33 (3H, brs), 0.8-1.9 (21H, m)Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3149, 2922, 2851, 1654,1460, 1059, 922 Mass spectrum (EI) m/z: 365 (M⁺) Anal. Calcd.(%) forC₂₁H₃₅NO2S: C, 69.00; H, 9.65; N, 3.83; S, 8.77 Found: C, 68.74; H,9.50; N, 3.83; S, 8.85 [α]_(D) ²⁴−1.3 (c 1.15, methanol)

EXAMPLE 192-Amino-2-methyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-olhydrochloride (exemplification compound No.1-1344)

[0846] The title compound was obtained according to a similar reactionto that described in Example 17 using2-amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-olobtained in Example 3.

[0847] Nuclear magnetic resonance spectrum (400 MHz, CD₃OD) δ ppm: 7.71(1H, d, J=4.0 Hz), 7.28-7.20 (2H, m), 7.20-7.10 (3H, m), 6.98 (1H, d,J=3.6 Hz), 3.62 (1H, d, J=7.6 Hz), 3.53 (1H, d, J=12.0 Hz), 3.04-2.88(4H, m), 2.64 (2H, t, J=7.2 Hz), 2.15-2.04 (1H, m), 2.04-1.92 (1H, m),1.78-1.62 (4H, m), 1.32 (3H, s) Infrared absorption spectrum ν_(max)cm⁻¹ (KBr): 3378, 2927, 1648, 1588, 1562, 1504, 1456, 1230, 1067, 827,748, 698, 578

EXAMPLE 202-Amino-2-methyl-4-{5-[5-(4-fluorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol(exemplification compound No.1-1348)

[0848] The title compound was obtained according to a similar reactionto that described in Example 17 using2-amino-2-methyl-4-{5-[5-(4-fluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-olobtained in Example 6.

[0849] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 7.51(1H, d, J=3.7 Hz), 7.08-7.17 (2H, m), 6.90-7.00 (2H, m), 6.83 (1H, d,J=3.7 Hz), 3.39 (1H, d, J=10.4 Hz), 3.33 (1H, d, J=10.4 Hz), 2.80-2.98(4H, m), 2.62 (2H, t, J=7.5 Hz), 1.60-1.90 (6H, m), 1.12 (3H, s)Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3178, 2935, 2858, 1645,1455, 1218, 1058

EXAMPLE 212-Amino-2-methyl-4-[5-(biphenyl-4-yl)acetylthiophen-2-yl]butan-1-ol(exemplification compound No.1-1326)

[0850] The title compound was obtained according to a similar reactionto that described in Example 17 using2-amino-2-methyl-4-[5-(biphenyl-4-yl)ethynylthiophen-2-yl]butan-1-olobtained in Example 6.

[0851] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 7.64(1H, d, J=3.7 Hz), 7.52-7.60 (4H, m), 7.30-7.47 (5H, m), 6.86 (1H, d,J=3.7 Hz), 4.18 (2H, s), 3.38 (1H, d, J=10.3 Hz), 3.33 (1H, d, J=10.3Hz), 2.84-2.98 (2H, m), 1.70-1.87 (2H, m), 1.12 (3H, s) Infraredabsorption spectrum ν_(max) cm⁻¹ (KBr): 3420, 2927, 1654, 1488, 1455,1234, 1058, 751

EXAMPLE 222-Amino-2-methyl-4-[5-(5-phenylpent-1-enyl)thiophen-2-yl]butan-1-olmaleate (exemplification compound No.1-670) EXAMPLE 22(a)4-Methyl-4-{2-[5-(5-phenylpent-1-enyl)thiophen-2-yl]}ethyloxazolidin-2-one

[0852] To 5-phenylpent-1-yne (0.38 ml, 2.58 mmol) was addedcatecholborane (500 mg, 1.72 mmol) at room temperature, and the mixturewas stirred at 60° C. for 3 hours. After the reaction solution wascooled down to room temperature, toluene (5.0 ml),4-[2-(5-bromothiophen-2-yl)]ethyl-4-methyloxazolidin-2-one (500 mg, 1.72mmol) obtained in Example 1(f), bis(triphenylphosphine)palladiumchloride (119 mg, 0.17 mmol), and sodium ethoxide (0.83 ml, 20% ethanolsolution) were added thereto at room temperature. The reaction mixturewas stirred for 2 hours at 60° C., cooled down to room temperature, andthen 1N sodium hydroxide was added thereto. The resulting mixture wasextracted with ethyl acetate, and the organic layer was washed withwater and then with a saturated aqueous sodium chloride solution. Afterthe ethyl acetate layer was dried over anhydrous sodium sulfate, thesolvent was evaporated in vacuo. The residue was purified by preparativethin-layer chromatography (elution solvent; hexane:ethyl acetate=1:1) togive the title compound (378 mg, 68% yield).

EXAMPLE 22(b)2-Amino-2-methyl-4-[5-(5-phenylpent-1-enyl)thiophen-2-yl]butan-1-olmaleate

[0853]4-Methyl-4-{2-[5-(5-phenylpent-1-enyl)thiophen-2-yl]}ethyloxazolidin-2-one(370 mg, 1.15 mmol) obtained in Example 22(a) was hydrolyzed accordingto a similar procedure to that described in Example 1(i) to give2-amino-2-methyl-4-[5-(5-phenylpent-1-enyl)thiophen-2-yl]butan-1-ol (205mg, 0.69 mmol). The title compound was obtained as a maleate (160 mg,34% yield) according to the general method for preparing maleates.

[0854] Nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:7.83-7.70 (2H, m), 7.38-7.12 (5H, m), 6.78 (1H, d, J=3.5 Hz), 6.71 (1H,d, J=3.5 Hz), 6.50 (1H, d, J=15.6 Hz), 6.02 (2H, s), 5.96-5.83 (1H, m),5.52 (2H, brs), 5.36-5.10 (1H, m), 3.51-3.38 (2H, m), 2.83-2.58 (4H, m),2.28-2.15 (2H, m), 1.88-1.63 (4H, m), 1.18 (3H, s) Infrared absorptionspectrum ν_(max) cm⁻¹ (KBr): 3206, 2932, 1579, 1497, 1386, 1357, 1194,1075, 1012, 865, 699, 570

EXAMPLE 232-Amino-2-methyl-4-[5-(5-cyclohexylpent-1-enyl)thiophen-2-yl]butan-1-ol(exemplification compound No.1-657)

[0855] The title compound was obtained according to a similar procedureto that described in Example 22.

[0856] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 6.64(1H, d, J=3.5 Hz), 6.61 (1H, d, J=3.5 Hz), 6.41 (1H, d, J=15.7 Hz),5.95-5.88 (1H, m), 3.36 (1H, d, J=10.5 Hz), 3.31 (1H, d, J=10.5 Hz),2.86-2.73 (2H, m), 2.29-2.08 (2H, m), 1.83-1.55 (8H, m), 1.52-1.33 (4H,m), 1.30-1.12 (6H, m), 1.11 (3H, s), 0.92-0.79 (2H, m) Infraredabsorption spectrum ν_(max) cm⁻¹ (KBr): 3328, 3275, 2921, 2850, 1610,1447, 1225, 1066, 1038, 957, 804, 504

EXAMPLE 242-Amino-2-methyl-4-[5-(6-cyclohexylhex-1-enyl)thiophen-2-yl]butan-1-olmaleate (exemplification compound No.1-683)

[0857] The title compound was obtained according to a similar procedureto that described in Example 22.

[0858] Nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:7.90-7.69 (2H, m), 6.77 (1H, d, J=3.4 Hz), 6.70 (1H, d, J=3.4 Hz), 6.47(1H, d, J=15.8 Hz), 6.04 (2H, s), 5.92-5.84 (1H, m), 5.55 (1H, brs),3.49-3.32 (2H, m), 2.85-2.71 (2H, m), 2.18-2.06 (2H, m), 1.96-1.53 (8H,m), 1.42-1.03 (14H, m), 0.93-0.78 (2H, m) Infrared absorption spectrumν_(max) cm⁻¹ (KBr): 3042, 2924, 2851, 1695, 1577, 1533, 1493, 1477,1387,1362, 1351, 1210, 1074, 866

EXAMPLE 252-Amino-2-methyl-4-[4-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-olhydrochloride (exemplification compound No.2-185) EXAMPLE 25(a)4-(5-Phenylpent-1-ynyl)thiophen-2-carboxaldehyde

[0859] 5-Phenylpent-1-yne (18.1 g, 126 mmol) was dissolved intetrahydrofuran (100 ml), and then 4-bromothiophen-2-carboxaldehyde(18.7 g, 98 mmol) in tetrahydrofuran (200 ml), triethylamine (150 ml,1.07 mmol), copper(I) iodide (962 mg, 5.05 mmol), anddichlorobis(triphenylphosphine)palladium (3.54 g, 5.04 mmol) were addedthereto, and the mixture was stirred at 50° C. for 4 hours under anitrogen atmosphere. After the reaction solution was filtered, thefiltrate was evaporated under reduced pressure. To the residue was addedether, and the solution was washed with water and a saturated aqueoussodium chloride solution, respectively. After the ether layer was driedover anhydrous sodium sulfate, the solvent was evaporated in vacuo. Theresidue was purified by chromatography on a silica gel column (elutionsolvent; hexane:ethyl acetate=100:1−10:1) to afford the title compound(19.4 g, 78% yield).

[0860] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 9.88(1H, s), 7.72 (1H, s), 7.71 (1H, s), 7.35-7.27 (2H, m), 7.24-7.16 (3H,m), 2.78 (2H, t, J=7.2 Hz), 2.41 (2H, t, J=7.2 Hz), 1.98-1.88 (2H, m)Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 2238, 1679, 1440, 1234,1157, 858, 748, 700, 665, 620 Mass spectrum (FAB) m/z: 255 ((M+H)⁺)

EXAMPLE 25(b) [4-(5-Phenylpent-1-ynyl)thiophen-2-yl]methanol

[0861] 4-(5-Phenylpent-1-ynyl)thiophen-2-carboxaldehyde (15.0 g, 59.0mmol) obtained in Example 25(a) was dissolved in methanol (150 ml),sodium borohydride (2.29 g, 60.5 mmol) was added thereto in an ice bath.The reaction mixture was stirred for 25 minutes in the ice bath, andthen the solvent was evaporated in vacuo. To the residue was addedwater, and the mixture was extracted with ethyl acetate, and then theethyl acetate layer was washed with a saturated aqueous sodium chloridesolution. After the ethyl acetate layer was dried over anhydrous sodiumsulfate, the solvent was evaporated under reduced pressure to afford thetitle compound (15.2 g, 99% yield).

[0862] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:7.34-7.27 (3H, m), 7.24-7.17 (3H, m), 6.98 (1H, s), 4.78 (2H, d, J=5.6Hz), 2.77 (2H, t, J=7.6 Hz), 2.39 (2H, t, J=7.2 Hz), 1.96-1.85 (2H, m),1.77 (1H, t, J=5.6 Hz)

[0863] Infrared absorption spectrum ν_(max) cm⁻¹ (liquid film): 3346,3026, 2940, 2861, 2235, 1602, 1496, 1455, 1355, 1182, 1141, 1013, 844,748, 700, 626 Mass spectrum (FAB) m/z: 256 (M⁺)

EXAMPLE 25(c) [4-(5-Phenylpent-1-ynyl)thiophen-2-yl]acetonitrile

[0864] [4-(5-Phenylpent-1-ynyl)thiophen-2-yl]methanol (4.68 g, 18.3mmol) obtained in Example 25(b) was dissolved in tetrahydrofuran (70ml), and phosphorus bromide (0.69 ml, 7.30 mmol) in tetrahydrofuran (20ml) was added dropwise thereto in an ice bath. After the dropping wasfinished, the reaction solution in the ice bath was stirred for 10minutes under a nitrogen atmosphere. To the reaction solution was addedice-cold water, and after the solution was extracted with ethyl acetate,the ethyl acetate layer was washed with a saturated aqueous sodiumhydrogencarbonate solution and then with a saturated aqueous sodiumchloride solution. After the ethyl acetate layer was dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure. The residue was dissolved in acetonitrile (120 ml), andtetraethylammonium cyanide (2.85 g, 18.3 mmol) was added thereto in theice bath followed by stirring for 1 hour at room temperature under anitrogen atmosphere. The reaction solution was poured into 5% aqueoussodium hydrogencarbonate solution, extracted with ethyl acetate, and theethyl acetate layer was washed with the saturated aqueous sodiumchloride solution. After the ethyl acetate layer was dried overanhydrous sodium sulfate, the solvent was evaporated in vacuo. Theresidue was purified by chromatography on a silica gel column (elutionsolvent; hexane:ethyl acetate: 20:1−15:1) to give the title compound(3.21 g, 66% yield).

[0865] Nuclear magnetic resonance spectrum (270 MHz, CDCl₃) δ ppm:7.15-7.35 (6H, m), 7.03 (1H, s), 3.86 (2H, s), 2.77 (2H, t, J=7.5 Hz),2.39 (2H, t, J=7.0 Hz), 1.83-1.98 (2H, m) Infrared absorption spectrumν_(max) cm⁻¹ (CHCl₃): 3691, 2946, 2236, 1603, 1497, 1454, 1416, 1361

EXAMPLE 25(d) 2-[4-(5-Phenylpent-1-ynyl)thiophen-2-yl]ethanol

[0866] [4-(5-Phenylpent-1-ynyl)thiophen-2-yl]acetonitrile (3.21 g, 12.1mmol) obtained in Example 25(c) was dissolved in ethanol (15 ml), andpotassium hydroxide (1.70 g, 30.2 mmol) in water (15 ml) was addedthereto in an ice bath followed by heating under reflux for 2 hours.After the reaction solution was acidified with 1N hydrochloric acid, theresulting solution was extracted with ethyl acetate. After the ethylacetate layer was dried over anhydrous sodium sulfate, the solvent wasevaporated under reduced pressure. The obtained residue was dissolved intetrahydrofuran (15 ml), and triethylamine (1.69 ml, 12.1 mmol) wasadded thereto. To the reaction solution was added dropwise ethylchloroformate (1.21 ml, 12.7 mmol) in tetrahydrofuran (15 ml) in an icebath, and the reaction mixture was stirred for 30 minutes under coolingwith ice in a nitrogen atmosphere. After this reaction solution wasfiltered, the obtained filtrate was added slowly to an aqueous solution(10 ml) of sodium borohydride (2.29 g, 60.5 mmol) in an ice bath, andthen the mixture was stirred for 3 days at room temperature. After thereaction solution was cooled down, acidified with 1N hydrochloric acid,and the resulting solution was extracted with ethyl acetate, and thenthe ethyl acetate layer was washed with a 1N aqueous sodium hydroxidesolution and then with a saturated aqueous sodium chloride solution. Theethyl acetate layer was dried over anhydrous sodium sulfate, and thesolvent was evaporated in vacuo. The residue was purified bychromatography on a silica gel column (elution solvent; hexane:ethylacetate=10:1−4:1) to afford the title compound (2.74 g, 84% yield).

[0867] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:7.15-7.30 (6H, m), 6.86 (1H, s), 3.85 (2H, t, J=6.2 Hz), 3.02 (2H, t,J=6.2 Hz), 2.77 (2H, t, J=7.6 Hz), 2.39 (2H, t, J=7.1 Hz), 1.85-1.95(2H, m) Infrared absorption spectrum ν_(max) cm⁻¹ (CHCl₃): 3620, 2947,1732, 1603, 1497, 1454, 1359, 1250, 1046

EXAMPLE 25(e) 2-(2-Iodoethyl)-4-(5-phenylpent-1-ynyl)thiophene

[0868] The title compound (3.45 g, 91% yield) was obtained according toa similar reaction to that described in Example 1(g) using2-[4-(5-phenylpent-1-ynyl)thiophen-2-yl]ethanol (2.69 g, 9.95 mmol)obtained in Example 25(d).

[0869] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:7.15-7.30 (6H, m), 6.84 (1H, s), 3.30-3.35 (4H, m), 2.77 (2H, t, J=7.6Hz), 2.39 (2H, t, J=7.0 Hz), 1.85-1.95 (2H, m) Infrared absorptionspectrum ν_(max) cm⁻¹ (CHCl₃): 2946, 2863, 1603, 1497, 1454, 1429, 1360,1172

EXAMPLE 25(f)2-Methyl-2-[4-(5-phenylpent-1-ynyl)thiophen-2-yl]ethylmalonic acidmonoethylester

[0870] Methylmalonic acid diethylester (1.57 g, 9.02 mmol) was dissolvedin dimethylformamide (30 ml), and sodium hydride (0.38 g, 9.47 mmol) wasadded thereto in an ice bath, and then the mixture was stirred for 1hour at room temperature in a nitrogen atmosphere. The dimethylformamidesolution (30 ml) of 2-(2-iodoethyl)-4-(5-phenylpent-1-ynyl)thiopheneobtained in Example 25(e) was added dropwise to the reaction solution inan ice bath, and the mixture was stirred for 4 hours at room temperatureunder a nitrogen atmosphere. After the reaction solution was cooleddown, acidified with 1N hydrochloric acid, and the resulting solutionwas extracted with ethyl acetate, and then the ethyl acetate layer waswashed with a 1N aqueous sodium hydroxide solution and then with asaturated aqueous sodium chloride solution. The ethyl acetate layer wasdried over anhydrous sodium sulfate, and the solvent was evaporated invacuo. The residue was partially purified by chromatography on a silicagel column (elution solvent; hexane:ethyl acetate=50:1−20:1). Theobtained mixture was dissolved in a mixture of ethanol (9 ml) and water(1 ml), and potassium hydroxide (0.80 g, 14.3 mmol) was added thereto inan ice bath, and then the reaction mixture was stirred for 3 days atroom temperature. After the reaction solution was acidified with 1Nhydrochloride acid, the resulting solution was extracted with ethylacetate. The ethyl acetate layer was dried over anhydrous sodiumsulfate, and the solvent was evaporated in vacuo. The residue waspurified by chromatography on a silica gel column (elution solvent;dichloromethane:methanol=50:1) to afford the title compound (1.02 g, 28%yield).

[0871] Nuclear magnetic resonance spectrum (500 MHz, CDCl₃) δ ppm:7.15-7.30 (6H, m), 6.79 (1H, s), 4.23 (2H, q, J=7.1 Hz), 2.60-2.85 (4H,m), 2.38 (2H, t, J=7.0 Hz), 2.20-2.32 (2H, m), 1.86-1.94 (2H, m), 1.53(3H, s), 1.29 (3H, t, J=7.1 Hz) Infrared absorption spectrum ν_(max)cm⁻¹ (CHCl₃): 3509, 2944, 1732, 1713, 1455, 1377, 1254, 1181, 1113

EXAMPLE 25(g)2-Methoxycarbonylamino-2-methyl-4-[4-(5-phenylpent-1-ynyl)thiophen-2-yl]butanoicacid ethylester

[0872] The title compound (0.85 g, 80% yield) was obtained according toa similar reaction to that described in Example 1(j) using2-methyl-2-[4-(5-phenylpent-1-ynyl)thiophen-2-yl]ethylmalonic acidmonoethylester (0.99 g, 2.48 mmol) obtained in Example 25(f).

[0873] Nuclear magnetic resonance spectrum (500 MHz, CDCl₃) δ ppm:7.15-7.30 (5H, m), 7.13 (1H, s), 6.75 (1H, s), 5.69 (1H, brs), 4.15-4.33(2H, m), 3.66 (3H, s), 2.50-2.80 (5H, m), 2.38 (2H, t, J=7.0 Hz),2.15-2.23 (1H, m), 1.87-1.93 (2H, m), 1.60 (3H, s), 1.25-1.30 (3H, m)Infrared absorption spectrum ν_(max) cm⁻¹ (CHCl₃): 3417, 2987, 2945,1719, 1504, 1453, 1323, 1077

EXAMPLE 25(h)4-Methyl-4-{2-[4-(5-phenylpent-1-ynyl)thiophen-2-yl]}ethyloxazolidin-2-one

[0874]2-Methoxycarbonylamino-2-methyl-4-[4-(5-phenylpent-1-ynyl)thiophen-2-yl]butanoicacid ethylester (0.82 g, 1.92 mmol) obtained in Example 25(g) wasdissolved in a mixture of ethanol (15 ml) and tetrahydrofuran (10 ml),and lithium chloride (0.24 g, 5.75 mmol) and sodium borohydride (0.22 g,5.75 mmol) were added thereto in an ice bath, and then the reactionmixture was stirred for 2 hours at 70° C. under a nitrogen atmosphere.After the reaction solution was acidified with 1N hydrochloride acid,the resulting solution was extracted with ethyl acetate, and the ethylacetate layer was washed with a saturated aqueous sodium chloridesolution. The ethyl acetate layer was dried over anhydrous sodiumsulfate, and the solvent was evaporated in vacuo. The residue waspurified by chromatography on a silica gel column (elution solvent;hexane:ethyl acetate=4:1−1:1) to give the title compound (0.65 g, 96%yield).

[0875] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:7.15-7.35 (6H, m), 6.79 (1H, s), 5.38 (1H, brs), 4.18 (1H, d, J=8.6 Hz),4.08 (1H, d, J=8.6 Hz), 2.80-2.90 (2H, m), 2.77 (2H, t, J=7.6 Hz), 2.38(2H, t, J=7.0 Hz), 1.85-2.00 (4H, m), 1.41 (3H, s) Infrared absorptionspectrum ν_(max) cm⁻¹ (CHCl₃): 3450, 2978, 2945, 1757, 1497, 1401, 1382,1249, 1046

EXAMPLE 25(i)2-Amino-2-methyl-4-[4-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-olhydrochloride

[0876]4-Methyl-4-{2-[4-(5-phenylpent-1-ynyl)thiophen-2-yl]}ethyloxazolidin-2-one(200 mg, 0.57 mmol) obtained in Example 25(h) was dissolved in a mixtureof tetrahydrofuran (1 ml) and methanol (2 ml), and a 5N aqueouspotassium hydroxide solution (2 ml) was added thereto in an ice bathfollowed by heating under reflux for 18 hours. To the reaction solutionwas added water, and the solution was extracted with dichloromethane.The dichloromethane layer was dried over anhydrous sodium sulfate, andthe solvent was evaporated in vacuo. The residue was dissolved in1,4-dioxane (2 ml), and a dioxane solution of 4N hydrochloric acid wasadded thereto in an ice bath, and then the solvent was evaporated underreduced pressure. The obtained white solid was washed with ether, anddried to give the title compound (165 mg, 80% yield).

[0877] Nuclear magnetic resonance spectrum (400 MHz, CD₃OD) δ ppm:7.15-7.30 (6H, m), 6.84 (1H, s), 3.61 (1H, d, J=11.5 Hz), 3.52 (1H, d,J=11.5 Hz), 2.80-2.95 (2H, m), 2.75 (2H, t, J=7.5 Hz), 2.35 (2H, t,J=7.0 Hz), 1.82-2.10 (4H, m), 1.32 (3H, s) Infrared absorption spectrumν_(max) cm⁻¹ (KBr): 3351, 3027, 2928, 1594, 1509, 1455, 1389, 1062

EXAMPLE 262-Amino-2-methyl-4-[4-(5-phenylpentyl)thiophen-2-yl]butan-1-olhydrochloride (exemplification compound No.2-39) EXAMPLE 26(a)4-Methyl-4-{2-[4-(5-phenylpentyl)thiophen-2-yl]}ethyloxazolidin-2-one

[0878]4-Methyl-4-{2-[4-(5-phenylpent-1-ynyl)thiophen-2-yl]}ethyloxazolidin-2-one(174 mg, 0.49 mmol) obtained in Example 25(h) was dissolved in ethanol(9 ml), and 5% palladium-charcoal (90 mg) was added thereto followed bystirring for 4 hours under a hydrogen atmosphere. After the catalyst wasfiltered out through Celite, the filtrate was evaporated to drynessunder reduced pressure. The residue was purified by chromatography on asilica gel column (elution solvent; hexane:ethyl acetate=1:1) to givethe title compound (164 mg, 93% yield).

[0879] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:7.25-7.30 (2H, m), 7.15-7.20 (3H, m), 6.70 (1H, s), 6.63 (1H, s), 5.33(1H, brs), 4.18 (1H, d, J=8.6 Hz), 4.07 (1H, d, J=8.6 Hz), 2.80-2.90(2H, m), 2.61 (2H, t, J=7.8 Hz), 2.53 (2H, t, J=7.7 Hz), 1.93-2.02 (2H,m), 1.55-1.70 (4H, m), 1.35-1.45 (5H, m) Infrared absorption spectrumν_(max) cm⁻¹ (CHCl₃): 3451, 2977, 2934, 2858, 1757, 1400, 1382, 1045

EXAMPLE 26(b)2-Amino-2-methyl-4-[4-(5-phenylpentyl)thiophen-2-yl]butan-1-olhydrochloride

[0880] The title compound (107 mg, 76% yield) was obtained according toa similar reaction to that described in Example 25(i) using4-methyl-4-{2-[4-(5-phenylpentyl)thiophen-2-yl]}ethyloxazolidin-2-one(136 mg, 0.38 mmol) obtained in Example 26(a).

[0881] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:7.10-7.30 (5H, m), 6.63 (1H, s), 6.61 (1H, s), 3.66 (2H, s), 2.80-2.95(2H, m), 2.58 (2H, t, J=7.7 Hz), 2.47 (2H, t, J=7.7 Hz), 2.00-2.18 (2H,m), 1.52-1.67 (4H, m), 1.25-1.45 (5H, m) Infrared absorption spectrumν_(max) cm⁻¹ (KBr): 3223, 2929, 2887, 1606, 1525, 1455, 1400, 1054

EXAMPLE 272-Amino-2-methyl-4-[4-(5-phenylpentanoyl)thiophen-2-yl]butan-1-olhydrochloride (exemplification compound No.2-343)

[0882]2-Amino-2-methyl-4-[4-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-olhydrochloride (178 mg, 0.49 mmol) obtained in Example 26(i) wasdissolved in methanol (2 ml), and 6N sulfuric acid (2 ml) was addedthereto followed by heating under reflux for 4 hours. After the reactionsolution was made alkaline with a 1N aqueous sodium hydroxide solution,the resulting solution was extracted with dichloromethane. Thedichloromethane layer was dried over anhydrous sodium sulfate, and thesolvent was evaporated in vacuo. The residue was dissolved in1,4-dioxane (2 ml), and the dioxane solution of 4N hydrochloric acid wasadded thereto in an ice bath, and then the solvent was evaporated underreduced pressure. The obtained white solid was washed with ether, anddried to give the title compound (100 mg, 53% yield).

[0883] Nuclear magnetic resonance spectrum (400 MHz, CD₃OD) δ ppm: 14(1H, s), 7.29 (1H, s), 7.10-7.27 (5H, m), 3.63 (1H, d, J=11.6 Hz), 3.53(1H, d, J=11.6 Hz), 2.85-3.00 (4H, m), 2.64 (2H, t, J=7.0 Hz), 1.92-2.13(2H, m), 1.67-1.75 (4H, m), 1.33 (3H, s) Infrared absorption spectrumν_(max) cm⁻¹ (KBr): 3361, 3026, 2939, 1666, 1591, 1456, 1154, 1072

EXAMPLE 282-Amino-2-ethyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-olmaleate (exemplification compound No.1-1909)

[0884] The title compound was obtained according to a similar reactionto that described in Example 1 using a racemic mixture of4-[2-(5-bromothiophen-2-yl)]ethyl-4-ethyloxazolidin-2-one as a startingmaterial.

[0885] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm: 6.90(1H, d, J=3.6 Hz), 6.72 (1H, d, J=3.6 Hz), 6.25 (2H, s), 3.61 (1H, d,J=11.7 Hz), 3.57 (1H, d, J=11.7 Hz), 2.75-2.90 (2H, m), 2.38 (2H, t,J=7.0 Hz), 1.88-2.06 (2H, m), 1.52-1.82 (9H, m), 1.12-1.37 (6H, m),0.85-1.04 (5H, m) Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3191,2922, 2851, 1576, 1521, 1386, 1362, 1193, 1068

EXAMPLE 292-Amino-2-ethyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-olmaleate (exemplification compound No.1-1764)

[0886] The title compound was obtained according to a similar reactionto that described in Example 11 using2-amino-2-ethyl-4-[5-(5-cyclohexylpent-2-ynyl)thiophen-1-yl]butan-1-olobtained in Example 28.

[0887] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm: 6.64(1H, d, J=3.7 Hz), 6.57 (1H, d, J=3.7 Hz), 6.25 (2H, s), 3.61 (1H, d,J=11.8 Hz), 3.57 (1H, d, J=11.8 Hz), 2.70-2.87 (4H, m), 1.88-2.05 (2H,m), 1.56-1.82 (9H, m), 1.10-1.38 (10H, m), 0.99 (3H, t, J=7.5 Hz),0.81-0.93 (2H, m) Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3196,2923, 2852, 1581, 1523, 1385, 1368, 1193, 1067, 1016

EXAMPLE 302-Amino-2-ethyl-4-[5-(5-cyclohexylpentanoyl)thiophen-2-yl]butan-1-olmaleate (exemplification compound No.1-2097)

[0888] The title compound was obtained according to a similar reactionto that described in Example 17 using2-amino-2-ethyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-olobtained in Example 28.

[0889] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm: 7.72(1H, d, J=3.7 Hz), 6.99 (1H, d, J=3.7 Hz), 6.25 (2H, s), 3.63 (1H, d,J=11.6 Hz), 3.59 (1H, d, J=11.6 Hz), 2.85-3.02 (4H, m), 1.94-2.12 (2H,m), 1.60-1.83 (9H, m), 1.10-1.42 (8H, m), 1.01 (3H, t, J=7.5 Hz),0.82-0.96 (2H, m) Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3395,2922, 2851, 1654, 1582, 1520, 1458, 1385, 1370, 1203, 1067

EXAMPLE 31(2R)-Amino-2-methyl-4-[5-(4-cyclohexyloxybut-1-ynyl)thiophen-2-yl]butan-1-olmaleate (exemplification compound No.1-1072)

[0890] The title compound was obtained according to a similar reactionto that described in Example 1 using4-[2-(5-bromothiophen-2-yl)]ethyl-4-methyloxazolidin-2-one as a startingmaterial. Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm:6.93 (1H, d, J=3.6 Hz), 6.73 (1H, d, J=3.6 Hz), 6.25 (2H, s), 3.57-3.67(3H, m), 3.51 (1H, d, J=11.6 Hz), 3.32-3.42 (1H, m), 2.78-2.95 (2H, m),2.63 (2H, t, J=6.7 Hz), 1.50-2.10 (7H, m), 1.1-1.37 (8H, m) Infraredabsorption spectrum ν_(max) cm⁻¹ (KBr): 3394, 2932, 2858, 1583, 1506,1386, 1367, 1194, 1104

EXAMPLE 322-Amino-2-methyl-4-[5-(4-cyclohexylmethoxyphenyl)thiophen-2-yl]butan-1-ol(exemplification compound No.1-1729)

[0891] The title compound was obtained according to a similar reactionto that described in Example 1 using4-[2-(5-bromothiophen-2-yl)ethyl-4-methyloxazolidin-2-one as a startingmaterial. Nuclear magnetic-resonance spectrum (400 MHz, CH₃OD) δ ppm:7.45 (2H, d, J=8.7 Hz), 7.02 (1H, d, J=3.6 Hz), 6.88 (2H, d, J=8.7 Hz),6.76 (1H, d, J=3.6 Hz), 3.77 (2H, d, J=6.3 Hz), 3.40 (1H, d, J=10.9 Hz),3.36 (1H, d, J=10.9 Hz), 2.91-2.79 (2H, m), 1.90-1.68 (8H, m), 1.41-1.08(5H, m), 1.11 (3H, s)

EXAMPLE 332-Amino-2-methyl-4-[5-(4-benzyloxyphenyl)thiophen-2-yl]butan-1-ol(exemplification compound No.1-1744)

[0892] The title compound was obtained according to a similar reactionto that described in Example 1 using4-[2-(5-bromothiophen-2-yl)ethyl-4-methyloxazolidin-2-one as a startingmaterial. Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm:7.51-7.27 (7H, m), 7.07 (1H, d, J=3.6 Hz), 6.98 (2H, d, J=8.7 Hz), 6.76(1H, d, J=3.6 Hz), 5.06 (2H, s), 3.44-3.38 (2H, m), 2.91-2.80 (2H, m),1.86-1.74 (2H, m), 1.11 (3H, s)

EXAMPLE 34

[0893](2R)-Amino-2-methyl-4-{5-[3-(4-methylphenoxy)propynyl]thiophen-2-yl{butan-1-olmaleate (exemplification compound No.1-1063)

[0894] The title compound was obtained according to a similar reactionto that described in Example 1.

[0895] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm: 1.31(3H, s), 1.88-2.10 (2H, m), 2.27 (3H, s), 2.80-2.95 (2H, m), 3.51 (1H,d, J=11.6 Hz), 3.60 (1H, d, J=11.6 Hz), 4.89 (2H, s), 6.25 (2H, s), 6.77(1H, d, J=3.6 Hz), 6.88 (2H, d, J=8.6 Hz), 7.05 (1H, d, J=3.6 Hz), 7.09(2H, d, J=8.6 Hz) Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3338,3211, 3006, 2923, 2229, 1583, 1511, 1372, 1228, 1018

EXAMPLE 35(2R)-Amino-2-methyl-4-{5-[3-(4-methylphenoxy)propyl]thiophen-2-yl}butan-1-olmaleate (exemplification compound No.1-391)

[0896] The title compound was obtained according to a similar reactionto that described in Example 11 using(2R)-amino-2-methyl-4-{5-[3-(4-methylphenoxy)propynyl]thiophen-2-yl)butan-1-ol maleate obtained in Example 34.

[0897] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm: 1.31(3H, s), 1.88-2.10 (4H, m), 2.25 (3H, s), 2.77-2.92 (2H, m), 2.94 (2H,t, J=7.5 Hz), 3.51 (1H, d, J=11.6 Hz), 3.60 (1H, d, J=11.6 Hz), 3.93(2H, t, J=6.2 Hz), 6.25 (2H, s), 6.62 (1H, d, J=3.3 Hz), 6.65 (1H, d,J=3.3 Hz), 6.77 (2H, d, J=8.5 Hz), 7.04.(2H, d, J=8.5 Hz) Infraredabsorption spectrum ν_(max) cm⁻¹ (KBr): 3412, 3028, 2947, 2926, 1577,1513, 1387, 1357, 1239, 1055

EXAMPLE 36(2R)-Amino-2-methyl-4-{5-[3-(3-methylphenoxy)propynyl]thiophen-2-yl}butan-1-oloxalate (exemplification compound No.1-2276)

[0898] The title compound was obtained according to a similar reactionto that described in Example 1.

[0899] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm: 1.31(3H, s), 1.90-2.10 (2H, m), 2.31 (3H, s), 2.82-2.96 (2H, m), 3.52 (1H,d, J=11.7 Hz), 3.60 (1H, d, J=11.7 Hz), 4.90 (2H, s), 6.73-6.85 (4H, m),7.05 (1H, d, J=3.6 Hz), 7.16 (1H, m) Infrared absorption spectrumν_(max) cm⁻¹ (KBr): 2923, 2575, 2226, 1621, 1583, 1559, 1489, 1290,1255, 1154, 1045

EXAMPLE 37(2R)-Amino-2-methyl-4-{5-[3-(4-ethylphenoxy)propynyl]thiophen-2-yl}butan-1-olmaleate (exemplification compound No.1-1064)

[0900] The title compound was obtained according to a similar reactionto that described in Example 1.

[0901] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm: 1.20(3H, t, J=7.6 Hz), 1.31 (3H, s), 1.88-2.10 (2H, m), 2.58 (2H, q, J=7.6Hz), 2.80-2.95 (2H, m), 3.51 (1H, d, J=11.5 Hz), 3.60 (1H, d, J=11.5Hz), 4.89 (2H, s), 6.25 (2H, s), 6.77 (1H, d, J=3.6 Hz), 6.90 (2H, d,J=8.6 Hz), 7.05 (1H, d, J=3.6 Hz), 7.12 (2H, d, J=8.6 Hz) Infraredabsorption spectrum ν_(max) cm⁻¹ (KBr): 3385, 2959, 2928, 2226, 1581,1510, 1384, 1232, 1020

EXAMPLE 38(2R)-Amino-2-methyl-4-{5-[3-(4-methylthiophenoxy)propynyl]thiophen-2-yl}butan-1-olmaleate (exemplification compound No.1-1068)

[0902] The title compound was obtained according to a similar reactionto that described in Example 1.

[0903] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm: 1.31(3H, s), 1.88-2.10 (2H, m), 2.42 (3H, s), 2.81-2.96 (2H, m), 3.51 (1H,d, J=11.5 Hz), 3.60 (1H, d, J=11.5 Hz), 4.92 (2H, s), 6.25 (2H, s), 6.78(1H, d, J=3.6 Hz), 6.96 (2H, d, J=8.9 Hz), 7.06 (1H, d, J=3.6 Hz), 7.27(2H, d, J=8.9 Hz) Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3401,2984, 2918, 2227, 1575, 1492, 1376, 1237, 1011

EXAMPLE 39(2R)-Amino-2-methyl-4-{5-[3-(3,5-dimethoxyphenoxy)propynyl]thiophen-2-yl}butan-1-olmaleate (exemplification compound No.1-2285)

[0904] The title compound was obtained according to a similar reactionto that described in Example 1.

[0905] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm: 1.31(3H, s), 1.90-2.10 (2H, m), 2.82-2.96 (2H, m), 3.51 (1H, d, J=11.6 Hz),3.61 (1H, d, J=11.6 Hz), 3.75 (6H, s), 4.89 (2H, s), 6.13 (1H, dd,J=2.2, 2.2 Hz), 6.43 (2H, d, J=2.2 Hz), 6.69 (2H, s), 6.78 (1H, d, J=3.6Hz), 7.07 (1H, d, J=3.6 Hz) Infrared absorption spectrum ν_(max) cm⁻¹(KBr): 3382, 2936, 2222, 1682, 1601, 1476, 1205, 1152, 1066

EXAMPLE 40(2R)-Amino-2-methyl-4-{5-[3-(3,4-dimethoxyphenoxy)propynyl]thiophen-2-yl}butan-1-olmaleate (exemplification compound No.1-2284)

[0906] The title compound was obtained according to a similar reactionto that described in Example 1.

[0907] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm: 1.31(3H, s), 1.88-2.10 (2H, m), 2.81-2.95 (2H, m), 3.51 (1H, d, J=11.4 Hz),3.61 (1H, d, J=11.4 Hz), 3.78 (3H, s), 3.81 (3H, s), 4.88 (2H, s), 6.25(2H, s), 6.54 (1H, dd, J=8.7, 2.7 Hz), 6.66 (1H, d, J=2.7 Hz), 6.78 (1H,d, J=3.6 Hz), 6.87 (1H, d, J=8.7 Hz), 7.05 (1H, d, J=3.6 Hz) Infraredabsorption spectrum ν_(max) cm⁻¹ (KBr): 3361, 2934, 2221, 1581, 1512,1385, 1369, 1228, 1196, 1023

EXAMPLE 41(2R)-Amino-2-methyl-4-{5-[3-(4-acetylphenoxy)propynyl]thiophen-2-yl}butan-1-ol(exemplification compound No.1-2288)

[0908] The title compound was obtained according to a similar reactionto that described in Example 1.

[0909] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm: 1.07(3H, s), 1.68-1.82 (2H, m), 2.56 (3H, s), 2.77-2.91 (2H, m), 3.33 (1H,d, J=11.0 Hz), 3.36 (1H, d, J=11.0 Hz), 5.05 (2H, s), 6.73 (1H, d, J=3.6Hz), 7.04 (1H, d, J=3.6 Hz), 7.10 (2H, d, J=9.0 Hz), 8.00 (2H, d, J=9.0Hz) Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3351, 3315, 3287,2916, 2878, 2734, 2229, 1673, 1599, 1376, 1364, 1253, 1174

EXAMPLE 42(2R)-Amino-2-methyl-4-{5-[3-(4-carboxyphenoxy)propynyl]thiophen-2-yl}butan-1-olhydrochloride (exemplification compound No.1-2289)

[0910] The title compound was obtained according to a similar reactionto that described in Example 1.

[0911] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm: 1.31(3H, s), 1.90-2.10 (2H, m), 2.82-2.96 (2H, m), 3.51 (1H, d, J=11.5 Hz),3.61 (1H, d, J=11.5 Hz), 5.04 (2H, s), 6.79 (1H, d, J=3.7 Hz), 7.05-7.11(3H, m), 7.99 (2H, d, J=8.8 Hz) Infrared absorption spectrum ν_(max)cm⁻¹ (KBr): 3383, 3064, 2226, 1699, 1604, 1508, 1379, 1233, 1170, 1002

EXAMPLE 43(2R)-Amino-2-methyl-4-{5-[3-(3-methoxylphenoxy)propynyl]thiophen-2-yl}butan-1-olmaleate (exemplification compound No.1-2283)

[0912] The title compound was obtained according to a similar reactionto that described in Example 1.

[0913] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm: 1.31(3H, s), 1.88-2.10 (2H, m), 2.80-2.96 (2H, m), 3.51 (1H, d, J=11.6 Hz),3.60 (1H, d, J=11.6 Hz), 3.77 (3H, s), 4.91 (2H, s), 6.25 (2H, s),6.52-6.61 (3H, m), 6.78 (1H, d, J=3.6 Hz), 7.06 (1H, d, J=3.6 Hz), 7.18(1H, t, J=8.4 Hz) Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3005,2940, 2223, 1583, 1493, 1387, 1362, 1284, 1191, 1153, 1080, 1045, 1020,866, 813, 758, 687, 565

EXAMPLE 44

[0914](2R)-Amino-2-methyl-4-{5-[4-(4-methylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-olmaleate (exemplification compound No.1-1139)

[0915] The title compound was obtained according to a similar reactionto that described in Example 1.

[0916] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm: 1.31(3H, s), 1.87-2.10 (2H, m), 2.26 (3H, s), 2.85 (2H, t, J=6.8 Hz),2.78-2.95 (2H, m), 3.51 (1H, d, J=11.6 Hz), 3.61 (1H, d, J=11.6 Hz),4.09 (2H, t, J=6.8 Hz), 6.25 (2H, s), 6.73 (1H, d, J=3.6 Hz), 6.82 (2H,d, J=8.4 Hz), 6.96 (1H, d, J=3.6 Hz), 7.07 (2H, d, J=8.4 Hz) Infraredabsorption spectrum ν_(max) cm⁻¹ (KBr): 3032, 2925, 2596, 1578, 1513,1388, 1359, 1293, 1244, 1205, 1176, 1079, 1039, 867, 812, 509

EXAMPLE 45(2R)-Amino-2-methyl-4-{5-[4-(4-fluorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol(exemplification compound No.1-1135)

[0917] The title compound was obtained according to a similar reactionto that described in Example 1.

[0918] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm: 1.15(3H, s), 1.72-1.89 (2H, m), 2.22 (3H, brs), 2.88 (2H, t, J=6.8 Hz),2.76-2.93 (2H, m), 3.37 (1H, d, J=10.8 Hz), 3.42 (1H, d, J=10.8 Hz),4.11 (2H, t, J=6.8 Hz), 6.64 (1H, d, J=3.6 Hz), 6.84-6.90 (2H, m),6.93-7.03 (3H, m) Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3356,3296, 3090, 2971, 2950, 2916, 2896, 2877, 2812, 2735, 1589, 1506, 1465,1389, 1289, 1245, 1219, 1203, 1154, 1065, 1039, 974, 923, 831, 819, 742,568, 523, 509

EXAMPLE 46 (2R)-Amino-2-methyl-4-{5-[3-(3,4-dimethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol maleate(exemplification compound No.1-2278)

[0919] The title compound was obtained according to a similar reactionto that described in Example 1.

[0920] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm: 1.31(3H, s), 1.90-2.09 (2H, m), 2.19 (3H, s), 2.23 (3H, s), 2.81-2.94 (2H,m), 3.31 (1H, s), 3.51 (1H, d, J=11.6 Hz), 3.61 (1H, d, J=11.6 Hz), 4.87(2H, s), 6.25 (2H, s), 6.70-6.78 (3H, m), 7.01-7.04 (2H, m) Infraredabsorption spectrum ν_(max) cm⁻¹ (liquid film): 3353, 3022, 2971, 2923,2226, 1579, 1500, 1385, 1368, 1287, 1249, 1205, 1165, 1120, 1077, 1039,930, 865, 806, 713, 573, 446

EXAMPLE 47(2R)-Amino-2-methyl-4-]2-(3-phenylpropyloxy)thiophen-5-yl]butan-1-oltartrate (exemplification compound No.1-2395) EXAMPLE 47(a)(2R)-Amino-2-methyl-4-thiophen-2-ylbutan-1-ol 1/2D-(−)-tartrate

[0921] (4R)-Methyl-4-[2-(thiophen-2-yl)]ethyloxazolidin-2-one (85% ee,7.30 g, 34.6 mmol) obtained in Example 56 was dissolved in the mixtureof tetrahydrofuran (35 ml) and methanol (70 ml), and a 5N aqueouspotassium hydroxide solution (70 ml) was added thereto in an ice bathfollowed by stirring for 2 days at 80° C. To the reaction solution wasadded dichloromethane, and the solution was washed with water. Thedichloromethane layer was dried over anhydrous magnesium sulfate, andthe solvent was evaporated under reduced pressure. The obtained residue(6.20 g) was dissolved in ethanol (60 ml), and D-(−)-tartaric acid (5.19g, 34.6 mmol) in ethanol (50 ml) was added thereto to give aprecipitate. The precipitate was filtered off to afford the crude titlecompound (7.56 g). The obtained crude target compound (7.54 g) wasrecrystallized from a mixture of ethanol (75 ml) and water (50 ml), andthe title compound (5.89 g, 98% ee) was-obtained. In addition, theobtained target compound (5.88 g) was recrystallized from ethanol (60ml) and water (54 ml) to afford the title compound (5.11 g, 99.7% ee).

[0922] Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3400, 3218,3126, 2937, 2596, 1599, 1530, 1400, 1124, 1077, 715 Anal. Calcd.(%) forC₉H₁₅NOS.0.5C₄H₄O₆: C, 50.95; H, 6.61; N, 5.40; S, 12.36 Found: C,50.68; H, 6.91; N. 5.38; S, 12.48 [α]_(D) ²⁴ −14(c 1.00, H₂O)

EXAMPLE 47(b) (2R)-Acetylamino-2-methyl-4-(thiophen-2-yl)butyl acetate

[0923] To (2R)-Amino-2-methyl-4-thiophen-2-ylbutan-1-ol1/2D-(−)-tartrate (5.11 g, 19.6 mmol) obtained in Example 47(a) wasadded a 1N aqueous sodium hydroxide solution (30 ml) in an ice bath, andthe resulting free compound was extracted with dichloromethane. Thedichloromethane layer was dried over anhydrous sodium sulfate, and thesolvent was evaporated in vacuo to give(2R)-amino-2-methyl-4-thiophen-2-ylbutan-1-ol (3.55 g, 98% yield). Tothe obtained (2R)-amino-2-methyl-4-(thiophen-2-yl)butan-1-ol (1.51 g,8.15 mmol) was added pyridine (30 ml), and then acetic anhydride (1.95ml, 20.7 mmol) and 4-(dimethylamino)pyridine (200 mg, 1.64 mmol) wereadded thereto in the ice bath followed by stirring for 2 hours at roomtemperature under a nitrogen atmosphere. The reaction solution waspoured into 1N hydrochloric acid (150 ml) in an ice bath, and thenextracted with ethyl acetate. The ethyl acetate layer was washedsuccessively with 1N hydrochloric acid and with a saturated aqueoussodium chloride solution. The ethyl acetate layer was dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by chromatography on a silica gelcolumn (elution solvent; hexane:ethyl acetate=3:1−1:2) to afford thetitle compound (2.15 g, 98% yield).

[0924] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 1.37(3H, s), 1.93 (3H, s), 1.94-2.10 (1H, m), 2.10 (3H,s), 2.24-2.38 (1H,m), 2.85 (2H, t, J=8.0 Hz), 4.18 (1H, d, J=11.6 Hz), 4.32 (1H, d, J=11.6Hz), 5.39 (1H, brs), 6.81 (1H, dd, J=1.2, 3.6 Hz), 6.92 (1H, dd, J=3.6,5.2 Hz), 7.12 (1H, dd, J=1.2, 5.2 Hz) Infrared absorption spectrumν_(max) cm⁻¹ (KBr): 3265, 3079, 2933, 2862, 1735, 1638, 1559, 1472,1441, 1374, 1318, 1241, 1179, 1039, 701, 616

EXAMPLE 47(c) (2R)-Acetylamino-2-methyl-4-(5-bromothiophen-2-ylbutylacetate

[0925] (2R)-Acetylamino-2-methyl-4-(thiophen-2-yl)butyl acetate (1.81 g,6.70 mmol) obtained in Example 47(b) was dissolved in dimethylformamide(20 ml), and N-bromosuccinimide (1.27 g, 7.11 mmol) was added thereto inan ice bath followed by stirring under a nitrogen atmosphere for 10minutes in an ice bath and then overnight at room temperature. Thereaction solution was poured into water, extracted with ethyl acetate,and the ethyl acetate layer was washed with a saturated aqueous sodiumchloride solution. The ethyl acetate layer was dried over anhydroussodium sulfate, and the solvent was evaporated in vacuo. The residue waspurified by chromatography on a silica gel column (elution solvent;hexane:ethyl acetate=3:1−1:2) to afford the title compound (2.32 g, 99%yield).

[0926] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 1.35(3H, s), 1.95 (3H, s), 1.95-2.08 (1H, m), 2.10 (3H,s), 2.24-2.37 (1H,m), 2.76 (2H, t, J=8.4 Hz), 4.15 (1H, d, J=11.2 Hz), 4.30 (1H, d, J=11.2Hz), 5.39 (1H, brs), 6.57 (1H, d, J=3.6 Hz), 6.84 (1H, d, J=3.6 Hz)Infrared absorption spectrum ν_(max) cm⁻¹ (liquid film): 3300, 3076,2980, 2937, 1740, 1657, 1544, 1466, 1446, 1373, 1242, 1045, 794, 604

EXAMPLE 47(d)(2R)-2-Amino-2-methyl-4-[2-(3-phenylpropyloxy)thiophen-5-yl]butan-1-oltartrate

[0927] To 3-phenyl-1-propanol (1 ml) was added sodium (0.06 g, 2.6mmol), and the mixture was heated slowly to 80° C. -90° C. and stirredat the temperature for 3 hours. After the reaction the solution wascooled gradually,(2R)-acetylamino-2-methyl-4-(5-bromothiophen-2-yl)butyl acetate (0.177g, 0.51 mmol) obtained in Example 47(c), potassium iodide (0.8 mg, 0.005mmol), and copper (II) oxide (21.0 mg, 0.26 mmol) were added thereto,and the reaction mixture was stirred for 19 hours at 90° C. Aftercooling the reaction solution, the solution was subjected successivelyto chromatography on a silica gel column (elution solvent;dichloromethane:methanol:triethylamine=10:1:0−100:10:1, V/V/V) and on analkaline silica gel column (elution solvent;dichloromethane:methanol=100:1, V/V) to give(2R)-2-amino-2-methyl-4-[2-(3-phenylpropyloxy)thiophen-5-yl]butan-1-ol(9.1 mg, 6% yield).

[0928] The obtained(2R)-2-amino-2-methyl-4-[2-(3-phenylpropyloxy)thiophen-5-yl]butan-1-ol(15.2.mg, 0.048 mmol) was dissolved in methanol (1 ml), and tartaricacid (4.5 mg, 0.049 mmol) was added thereto followed by stirring for 1.5hours at room temperature. The solvent was concentrated under reducedpressure, and then ethyl acetate was added thereto to precipitatecrystals, which were filtered off. The precipitate was washed with ethylacetate and dried to afford the title compound (18.5 mg, 95% yield).

[0929] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm:1.30(3H, s), 1.86-2.07(4H, m), 2.68-2.79(4H, m), 3.51(1H, d, J=11.6 Hz),3.59(1H, d, J=11.6 Hz), 3.97(2H, t, J=6.5 Hz), 6.00(1H, d, J=3.7 Hz),6.44(1H, d, J=3.7 Hz), 7.14-7.28(5H, m) Mass spectrum (ESI) m/z: 342 ((M+Na)⁺), 320 ((M +H)⁺)

EXAMPLE 48(2R)-Amino-2-methyl-4-{5-[3-(3-acetylphenoxy)propynyl]thiophen-2-yl}butan-1-oloxalate (exemplification compound No.1-2287)

[0930] The title compound was obtained according to a similar reactionto that described in Example 1.

[0931] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm: 1.31(3H, s), 1.88-2.10 (2H, m), 2.60 (3H, s), 2.82-2.95 (2H, m), 3.51 (1H,d, J=11.6 Hz), 3.60 (1H, d, J=11.6 Hz), 5.02 (2H, s), 6.78 (1H, d, J=3.6Hz), 7.06 (1H, d, J=3.6 Hz), 7.26 (1H, m), 7.44 (1H, m), 7.61-7.67 (2H,m) Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3346, 3213, 2929,2224, 1679, 1595, 1582, 1277, 1205, 721

EXAMPLE 49(2R)-Amino-2-methyl-4-[5-(5-phenylpent-1-ypyl)thiophen-2-yl]butan-1-oloxalate (exemplification compound No.1-824) EXAMPLE 49(a)(2R)-Acetylamino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butylacetate

[0932] (2R)-Acetylamino-2-methyl-4-(5-bromothiophen-2-yl)butyl acetate(1.60 g, 4.59 mmol) obtained in Example 47(c) was dissolved indimethylformamide (16 ml), and 5-phenylpent-1-yne (1.99 g, 13.8 mmol),triethylamine (6.40 ml, 45.9 mmol), copper(I) iodide (175 mg, 0.92mmol), and dichlorobis(triphenylphosphine)palladium (322 mg, 0.46 mmol)were added thereto followed by stirring for 2 hours at 80° C. under anitrogen atmosphere. The reaction solution was poured into water,extracted with ethyl acetate, and after the ethyl acetate layer wasdried over anhydrous magnesium sulfate, the solvent was evaporated invacuo. The residue was purified by chromatography on a silica gel column(elution solvent; hexane:ethyl acetate=2:1−2:3) to give the titlecompound (1.41 g, 75% yield).

[0933] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 1.36(3H, s), 1.85-2.05 (3H, m), 1.94 (3H, s), 2.10 (3H, s), 2.25-2.35 (1H,m), 2.43 (2H, t, J=7.0 Hz), 3.70-3.80 (4H, m), 4.17 (1H, d, J=11.2 Hz),4.31 (1H, d, J=11.2 Hz), 5.38 (1H, brs), 6.64 (1H, d, J=3.6 Hz), 6.94(1H, d, J=3.6 Hz), 7.15-7.42 (5H, m) Infrared absorption spectrumν_(max) cm⁻¹ (CHCl₃): 3443, 2946, 2862, 1737, 1681, 1511, 1374, 1251,1042

EXAMPLE 49(b)(2R)-Amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-oloxalate

[0934](2R)-Acetylamino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butylacetate (1.40 g 3.40 mmol) obtained in Example 49(a) was dissolved in 14ml of a mixture solution (tetrahydrofuran:methanol:water=1:1:1), andlithium hydroxide monohydrate (1.43 g, 34.0 mmol) was added theretofollowed by stirring for 4 hours at 50° C. The reaction solution waspoured into water, extracted with dichloromethane, and after thedichloromethane layer was dried over anhydrous sodium sulfate, thesolvent was evaporated under reduced pressure. The residue was purifiedby chromatography on a silica gel column (elution solvent;dichloromethane:methanol:ammonia water=20:1:0−10:1:0.1) to afford(2R)-amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol(1.11 g, 100% yield). The obtained(2R)-amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol(360 mg, 1.10 mmol) was dissolved in methanol, and oxalic acid (99 mg,1.10 mmol) was added thereto to precipitate crystals. The crystals wererecrystallized from methanol to afford the title compound (394 mg, 86%yield) as white crystals.

[0935] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm: 1.31(3H, s), 1.82-2.10 (4H, m), 2.40 (2H, t, J=7.0 Hz), 2.75 (2H, t, J=7.5Hz), 2.80-2.95 (2H, m), 3.52 (1H, d, J=11.5 Hz), 3.61 (1H, d, J=11.5Hz), 6.73 (1H, d, J=3.6 Hz), 6.94 (1H, d, J=3.6 Hz), 7.13-7.30 (5H, m)Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3383, 3106, 3026, 2980,2942, 2622, 2514, 1721, 1609, 1539, 1198, 699 Mass spectrum (FAB) m/z:328 ((M +H)⁺) (acid free form) Anal. Calcd.(%) forC₂₀H₂₅NOS.C₂H₂O₄.0.2H₂O: C, 62.75; H, 6.55; N, 3.32; S, 7.61 Found: C,62.50; H, 6.29; N, 3.39; S, 7.70 [α]_(D) ²⁵ −0.9 (c 1.00, methanol)

EXAMPLE 50(2R)-Amino-2-methyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-oloxalate (exemplification compound No.1-1344)

[0936](2R)-Amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol(387 mg, 1.18 mmol) obtained in Example 49 was dissolved in methanol (4ml), and 6N sulfuric acid (4 ml) was added thereto followed by heatingunder reflux for 4 hours. The reaction solution was cooled to 0° C. andmade alkaline (pH 14) with a 1N aqueous sodium hydroxide solution, andthe resulting solution was extracted with dichloromethane. Thedichloromethane layer was dried over anhydrous sodium sulfate, and thesolvent was evaporated in vacuo. The residue was purified bychromatography on a silica gel column (Chromatorex NH (100-200 mesh))(elution solvent; dichloromethane:methanol=1:0−50:1) to afford(2R)-amino-2-methyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-ol(336 mg, 82% yield). This compound was dissolved in methanol, and oxalicacid (88 mg, 0.97 mmol) was added thereto to precipitate crystals. Thecrystals were recrystallized from methanol to afford-the title compound(332 mg, 78% yield) as white crystals.

[0937] Nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:1.19 (3H, s), 1.55-1.67 (4H, m), 1.80-1.98 (2H, m), 2.60 (2H, t, J=6.7Hz), 2.83-2.96 (4H, m), 3.40 (1H, d, J=11.3 Hz), 3.47 (1H, d, J=11.3Hz), 7.00 (1H, d, J=3.7 Hz), 7.13-7.22 (3H, m), 7.23-7.31 (2H, m), 7.80(1H, d, J=3.7 Hz) Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3126,2942, 2657, 1915, 1718, 1649, 1609, 1547, 1445, 1205, 700 Mass spectrum(FAB) m/z: 346 ((M +H)⁺) (acid free form) Anal. Calcd.(%) forC₂₀H₂₇NO₂S.C₂H₂O₄.0.5H₂O: C, 59.44; H, 6.80; N, 3.15; S, 7.21 Found: C,59.62; H, 6.53; N, 3.31; S, 7.43

EXAMPLE 51(2R)-Amino-2-methyl-4-[5-(5-phenylpentyl)thiophen-2-yl]butan-1-oloxalate (exemplification compound No.1-152)

[0938](2R)-Acetylamino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butylacetate (337 mg, 0.82 mmol) obtained in Example 49(a) was dissolved inmethanol (17 ml), and 10% palladium-charcoal (170 mg) was added theretofollowed by stirring for 16 hours under a hydrogen atmosphere. After thecatalyst was filtered out through Celite, the filtrate was evaporated todryness under reduced pressure to give(2R)-acetylamino-2-methyl-4-[5-(5-phenylpentyl)thiophen-2-yl]butylacetate (318 mg, 93% yield). The obtained(2R)-acetylamino-2-methyl-4-[5-(5-phenylpentyl)thiophen-2-yl]butylacetate (298 mg, 0.72 mmol) was dissolved in 6 ml of a mixture solvent(tetrahydrofuran:methanol:water=1:1:1), and lithium hydroxidemonohydrate (301 mg, 7.17 mmol) was added thereto followed by stirringfor 6 hours at 50° C. The reaction solution was poured into water,extracted with ethyl acetate, and after the ethyl acetate layer wasdried over anhydrous sodium sulfate, the solvent was evaporated invacuo. The residue (243 mg) was dissolved in methanol, and oxalic acid(65 mg, 0.72 mmol) was added thereto to precipitate crystals. Thecrystals were filtered off to afford the title compound (251 mg, 83%yield) as white crystals.

[0939] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm: 1.31(3H, s), 1.32-1.42 (2H, m), 1.58-1.70 (4H, m), 1.88-2.08 (2H, m), 2.59(2H, t, J=7.6 Hz), 2.74 (2H, t, J=7.4 Hz), 2.75-2.91 (2H, m), 3.52 (1H,d, J=11.6 Hz), 3.61 (1H, d, J=11.6 Hz), 6.56 (1H, d, J=3.3 Hz), 6.63(1H, d, J=3.3 Hz), 7.09-7.17 (3H, m), 7.19-7.27 (2H, m) Infraredabsorption spectrum ν_(max) cm⁻¹ (KBr): 3458, 3134, 2929, 2855, 2595,1724, 1642, 1543, 1219, 710

EXAMPLE 52(2R)-Amino-2-methyl-4-{5-[3-(4-chlorophenoxy)propynyl]thiophen-2-yl]butan-1-oloxalate (exemplification compound No.1-2273) EXAMPLE 52(a)(2R)-Acetylamino-2-methyl-4-[5-(3-hydroxypropynyl)thiophen-2-yl]butylacetate

[0940] (2R)-Acetylamino-2-methyl-4-(5-bromothiophen-2-yl)butyl acetate(1.38 g, 3.95 mmol) obtained in Example 47(c) was dissolved indimethylformamide (20 ml), and then propargylalcohol (0.69 ml, 11.9mmol), triethylamine (5.60 ml, 40.1 mmol), copper(I) iodide (76 mg, 0.40mmol), and dichlorobis(triphenylphosphine)palladium (276 mg, 0.39 mmol)were added thereto followed by stirring for 1 hour at 80° C. under anitrogen atmosphere. The reaction solution was poured into water,extracted with ethyl acetate, and after the ethyl acetate layer wasdried over anhydrous sodium sulfate, the solvent was evaporated invacuo. The residue was purified by chromatography on a silica gel column(elution solvent; hexane:ethyl acetate=3:1−1:3) to afford the titlecompound (685 mg, 54% yield) as a white crystalline solid.

[0941] Nuclear magnetic resonance spectrum (500 MHz, CDCl₃) δ ppm: 1.35(3H, s), 1.91 (1H, brs), 1.94 (3H, s), 1.97-2.05 (1H, m), 2.10 (3H, s),2.27-2.35 (1H, m), 2.75-2.82 (2H, m), 4.16 (1H, d, J=11.2 Hz), 4.31 (1H,d, J=11.2 Hz), 4.49 (2H, s), 5.43 (1H, brs), 6.66 (1H, d, J=3.6 Hz),7.02 (1H, d, J=3.6 Hz) Infrared absorption spectrum λ_(max) cm⁻¹ (KBr):3295, 3077, 2981, 2217, 1740, 1644, 1556, 1373, 1251, 1028

EXAMPLE 52(b)(2R)-Amino-2-methyl-4-{5-[3-(4-chlorolphenoxy)propnypyl]thiophen-2-yl]butan-1-oloxalate

[0942](2R)-Acetylamino-2-methyl-4-[5-(3-hydroxypropynyl)thiophen-2-yl]butylacetate (285 mg, 0.88 mmol) obtained in Example 52(a) and 4-chlorophenol(136 mg, 1.06 mmol) were dissolved in anhydrous tetrahydrofuran (5 ml),and then azodicarboxylic acid diethylester (230 mg, 1.32 mmol) andtriphenylphosphine (346 mg, 1.32 mmol) were added thereto in an ice bathfollowed by stirring for 4 hours at room temperature. Into the reactionmixture was poured water, and the resulting solution was extracted withethyl acetate. The ethyl acetate layer was dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by chromatography on a silica gelcolumn (elution solvent; hexane:ethyl acetate=2:1−1:3) to give(2R)-acetylamino-2-methyl-4-{5-[3-(4-chlorophenoxy)propynyl]thiophen-2-yl}butylacetate (195 mg, 51% yield) as a yellow oil. This product was dissolvedin 6 ml of a mixture solvent (tetrahydrofuran:methanol:water=1:1:1), andlithium hydroxide monohydrate (370 mg, 8.82 mmol) was added theretofollowed by stirring for 6 hours at 50° C. The reaction solution waspoured into water, extracted with dichloromethane, and after thedichloromethane layer was dried over anhydrous sodium sulfate, thesolvent was evaporated in vacuo. The residue (175 mg, 0.50 mmol) wasdissolved in ethyl acetate (5 ml), and oxalic acid (45 mg, 0.50 mmol)was added thereto to precipitate crystals. The crystals were filteredoff to afford the title compound (198 mg, 86% yield) as white crystals.

[0943] Nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:1.18 (3H, s), 1.7-2.0 (2H, m), 2.84 (2H, t, J=8.7 Hz), 3.43 (2H, m),5.07 (2H, s), 6.83 (1H, d, J=3.6 Hz), 7.05 (2H, d, J=9.0 Hz), 7.19 (1H,d, J=3.6 Hz), 7.37 (2H, d, J=9.0 Hz) Infrared absorption spectrumν_(max) cm⁻¹ (KBr): 3416, 1719, 1597, 1490, 1375, 1241, 1201, 1092,1006, 830 Mass spectrum (FAB) m/z: 350 ((M +H)⁺) (acid free form) Anal.Calcd.(%) for C₁₈H₂₀NO₂SCl.C₂H₂O₄: C, 54.61; H, 5.04; N, 3.18; S, 7.29;Cl, 8.06 Found: C, 54.61; H, 5.04; N, 3.01; S, 7.16; Cl, 7.77

EXAMPLE 53 (2R)-Amino-2-methyl-4-[5-(1-hydroxy-5-phenylpentyl)thiophen-2-yl]butan-1-ol oxalate(exemplification compound No.1-1686)

[0944](2R)-Amino-2-methyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-ol(130 mg, 0.38 mmol) obtained in Example 50 was dissolved in methanol (3ml), and sodium borohydride (17 mg, 0.45 mmol) was added thereto in anice bath followed by stirring for 1 hour at room temperature. To thereaction solution was added water in the ice bath, and the resultingsolution was extracted with ethyl acetate. The ethyl acetate layer waswashed with a saturated aqueous sodium chloride solution, dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was dissolved in methanol, andoxalic acid (34 mg, 0.38 mmol) was added thereto, and the solvent wasevaporated in vacuo. To the residue was added ethanol (3 ml), and theresulting precipitate was filtered off to give the title compound (95mg, 58% yield) as a white crystalline solid.

[0945] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm:1.25-1.50 (2H, m), 1.30 (3H, s), 1.58-1.68 (2H, m), 1.70-2.08 (4H, m),2.52-2.64 (2H, m), 2.80-2.94 (2H, m), 3.53 (1H, d, J=11.7 Hz), 3.59 (1H,d, J=11.7 Hz), 4.74 (1H, t, J=6.8 Hz), 6.69 (1H; d, J=3.6 Hz), 6.74 (1H,d, J=3.6 Hz), 7.08-7.27 (5H, m) Infrared absorption spectrum ν_(max)cm⁻¹ (KBr): 3357, 2933, 2857, 1579, 1496, 1454, 1310, 1070, 699

EXAMPLE 54(2R)-Amino-2-methyl-4-[5-(4-phenylbut-1-ynyl)thiophen-2-yl]butan-1-oloxalate (exemplification compound No.1-756)

[0946] The title compound was obtained according to a similar reactionto that described in Example 49 using(2R)-acetylamino-2-methyl-4-(5-bromothiophen-2-yl)butyl acetate and4-phenylbut-1-yne.

[0947] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm: 1.31(3H, s), 1.88-2.09 (2H, m), 2.68 (2H, t, J=7.3 Hz), 2.78-2.93 (4H, m),3.52 (1H, d, J=1 1.6 Hz), 3.61 (1H, d, J=11.6 Hz), 6.72 (1H, d, J=3.6Hz), 6.88 (1H, d, J=3.6 Hz), 7.16-7.31 (5H, m) Infrared absorptionspectrum ν_(max) cm⁻¹ (KBr): 3204, 3110, 3026, 2981, 2929, 2887, 1719,1608, 1541, 1202, 699

EXAMPLE 55(2R)-Amino-2-methyl-4-[5-(4-phenylbutanoyl)thiophen-2-yl]butan-1-oloxalate (exemplification compound No.1-1330)

[0948] The title compound was obtained according to a similar reactionto that described in Example 50 using(2R)-amino-2-methyl-4-[5-(4-phenylbut-1-ynyl)thiophen-2-yl]butan-1-olobtained in Example 54.

[0949] Nuclear magnetic resonance spectrum (400 MHz, DMSO-d₆) δ ppm:1.19 (3H, s), 1.82-1.98 (4H, m), 2.62 (2H, t, J=7.7 Hz), 2.85-2.97 (4H,m), 3.39 (1H, d, J=1 1.7 Hz), 3.45 (1H, d, J=11.7 Hz), 7.00 (1H, d,J=3.8 Hz), 7.15-7.33 (5H,m), 7.76 (1H, d, J=3.8 Hz) Infrared absorptionspectrum ν_(max) cm⁻¹ (KBr): 3410, 3210, 2941, 2653, 2576, 1665, 1641,1530, 1452, 1325

EXAMPLE 56(2R)-Amino-2-methyl-4-[5-(4-cyclohexylbut-1-ynyl)thiophen-2-yl]butan-1-ol(exemplification compound No.1-743)

[0950] The title compound was obtained according to a similar reactionto that described in Example 1.

[0951] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm:0.87-0.99 (2H, m), 1.08 (3H, s), 1.11-1.50 (6H, m), 1.62-1.81 (7H, m),2.41 (2H, t, J=7.2 Hz), 2.74-2.88 (2h, m), 3.34 (1H, d, J=11.0 Hz), 3.37(1H, d, J=11.0 Hz), 6.66 (1H, d, J=3.6 Hz), 6.87 (1H, d, J=3.6 Hz)Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3334, 3269, 3153, 2922,2851, 1618, 1449, 1060, 804

EXAMPLE 57(2R)-Amino-2-methyl-4-[5-(4-cyclohexylbutyl)thiophen-2-yl]butan-1-ol(exemplification compound No.1-71)

[0952] The title compound was obtained according to a similar reactionto that described in Example 11 using(2R)-amino-2-methyl-4-[5-(4-cyclohexylbut-1-ynyl)thiophen-2-yl]butan-1-olobtained in Example 56.

[0953] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm:0.80-0.95 (2H, m), 1.08 (3H, s), 1.10-1.40 (8H, m), 1.54-1.81 (9H, m),2.68-2.87 (4H, m), 3.34 (1H, d, J=10.9 Hz), 3.37 (1H, d, J=10.9 Hz),6.53 (1H, d, J=3.2 Hz), 6.58 (1H, d, J=3.2 Hz) Infrared absorptionspectrum ν_(max) cm⁻¹ (KBr): 3333, 3269, 3170, 2923, 2850, 1619, 1461,1447, 1059, 801

EXAMPLE 58(2R)-Amino-2-methyl-4-[5-(4-cyclohexylbutanoyl)thiophen-2-yl]butan-1-ol(exemplification compound No.1-1 329)

[0954] The title compound was obtained according to a similar reactionto that described in Example 17 using(2R)-amino-2-methyl-4-[5-(4-cyclohexylbut-1-ynyl)thiophen-2-yl]butan-1-olobtained in Example 56.

[0955] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm:0.83-0.97 (2H, m), 1.09 (3H, s), 1.10-1.33 (6H, m), 1.61-1.86 (9H, m),2.82-3.00 (4H, m), 3.35 (1H, d, J=10.9 Hz), 3.39 (1H, d, J=10.9 Hz),6.94 (1H, d, J=3.7 Hz), 7.69 (1H, d, J=3.7 Hz) Infrared absorptionspectrum ν_(max) cm⁻¹ (KBr): 3333, 3268, 3142, 2921, 2849, 1648, 1457,1208, 1057, 923, 816

EXAMPLE 592-Amino-2-methyl-4-[5-(3-cyclohexylmethoxypropynyl)thiophen-2-yl]butan-1-olmaleate (exemplification compound No.1-1185)

[0956] The title compound was obtained according to a similar reactionto that described in Example 1.

[0957] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm:0.92-1.04 (2H, m), 1.13-1.37 (3H, m), 1.31 (3H, s), 1.53-1.82 (6H, m),1.89-2.11 (2H, m), 2.82-2.96 (2H, m), 3.35 (2H, d, J=6.4 Hz), 3.51 (1H,d, J=1 1.5 Hz), 3.61 (1H, d, J=1 1.5 Hz), 4.87 (2H, s), 6.25 (2H, s),6.78 (1H, d, J=3.6 Hz), 7.05 (1H, d, J=3.6 Hz) Infrared absorptionspectrum ν_(max) cm⁻¹ (KBr): 2924, 2852, 2218, 1577, 1496, 1386, 1356,1195, 1089, 866

EXAMPLE 60(2R)-Amino-2-methyl-4-[5-(4-cyclohexyloxybutyl)thiophen-2-yl]butan-1-olmaleate (exemplification compound No.1-400)

[0958] The title compound was obtained according to a similar reactionto that described in Example 11 using(2R)-amino-2-methyl-4-[5-(4-cyclohexylbut-1-yl)thiophen-2-yl]butan-1-olin Example 31.

[0959] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm:1.15-1.35 (5H, m), 1.31 (3H, s), 1.50-1.80 (7H, m), 1.85-2.08 (4H, m),2.73-2.92 (4H, m), 3.20-3.30 (1H, m), 3.45-3.55 (3H, m), 3.60 (1H, d,J=11.6 Hz), 6.25 (2H, s), 6.59(1H, d, J=3.3 Hz), 6.64 (1H, d, J=3.3 Hz)Infrared absorption spectrum ν_(max) cm-¹ (KBr): 2931, 2856, 1577, 1490,1471, 1459, 1388, 1357, 1108, 1081, 868

EXAMPLE 61(2R)-Amino-2-methyl-4-{5-[4-(4-fluorophenoxy)butyl]thiophen-2-yl}butan-1-ol(exemplification compound No.1-463)

[0960] The title compound was obtained according to a similar reactionto that described in Example 11 using(2R)-amino-2-methyl-4-{5-[4-(4-fluorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-olobtained in Example 45.

[0961] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm: 1.08(3H, s), 1.70-1.85 (6H, m), 2.73-2.88 (4H, m), 3.34 (1H, d, J=10.9 Hz),3.38 (1H, d, J=10.9 Hz), 3.94 (2H, t, J=5.9 Hz), 6.58 (1H, d, J=3.7 Hz),6.60 (1H, d, J=3.7 Hz), 6.83-6.90 (2H, m), 6.93-7.00 (2H, m) Infraredabsorption spectrum ν_(max) cm⁻¹ (KBr): 3333, 3268, 3162, 2940, 2865,1509, 1474, 1244, 1220, 1060, 830, 763

EXAMPLE 62(2R)-Amino-2-methyl-4-{5-[4-(4-methoxyphenoxy)butyl]thiophen-2-yl}butan-1-ol(exemplification compound No.1-479)

[0962] The title compound was obtained according to a similar reactionto that described in Example 26 using(4R)-methyl-4-{2-[4-(4-methoxyphenoxy)but-1-ynyl]}ethyloxazolidineobtained in Example 1(h).

[0963] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm: 1.08(3H, s), 1.68-1.84 (6H, m), 2.73-2.87 (4H, m), 3.34 (1H, d, J=10.8 Hz),3.38 (1H, d, J=10.8 Hz), 3.72 (3H, s), 3.91 (2H, t, J=6.0 Hz), 6.58 (1H,d, J=3.1 Hz), 6.60 (1H, d, J=3.1 Hz), 6.81 (4H, s) Infrared absorptionspectrum ν_(max) cm⁻¹ (KBr): 3335, 3273 3183, 2945, 2868, 1514, 1473,1233, 1045, 825, 735

EXAMPLE 63(2R)-Amino-2-methyl-4-[5-(4-benzyloxybut-1-ynyl)thiophen-2-yl]butan-1-oloxalate (exemplification compound No.1-1266)

[0964] The title compound was obtained according to a similar reactionto that described in Example 1.

[0965] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm: 1.31(3H, s), 1.89-2.10 (2H, m), 2.70 (2H, t, J=6.8 Hz), 2.80-2.94 (2H, m),3.52 (1H, d, J=11.6 Hz), 3.61 (1H, d, J=11.6 Hz), 3.64 (2H, t, J=6.8Hz), 4.57 (2H, s), 6.74 (1H, d, J=3.6 Hz), 6.94 (1d, J=3.6 Hz),7.23-7.39 (5H, m) Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3358,3028, 2926, 2544, 1719, 1702, 1605, 1496, 1468, 1454, 1402, 1279, 1204,1105, 806, 739, 720, 699, 500 Mass spectrum (FAB) m/z: 344 ((M +H)⁺)(acid free form)

EXAMPLE 64(2R)-Amino-2-methyl-4-[5-(4-benzyloxybutyl)thiophen-2-yl]butan-1-olmaleate (exemplification compound No.1-594)

[0966] The title compound was obtained according to a similar reactionto that described in Example 11 using(2R)-amino-2-methyl-4-[5-(4-benzyloxybut-1-ynyl)thiophen-2-yl]butan-1-olobtained in Example 63.

[0967] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm: 1.31(3H, s), 1.59-1.76 (4H, m), 1.88-2.08 (2H, m), 2.76 (2H, t, J=7.2 Hz),2.79-2.91 (2H, m), 3.49 (2H, t, J=6.4 Hz), 3.51 (1H, d, J=11.6 Hz), 3.60(1H, d, J=l11.6 Hz), 4.48 (2H, s), 6.25 (2H, s), 6.58 (1H, d, J=3.6 Hz),6.64 (1H, d, J=3.6 Hz), 7.23-7.38 (5H, m) Infrared absorption spectrumν_(max) cm⁻¹ (KBr): 2935, 2862, 1579, 1496, 1386, 1363, 1195, 1104,1077, 1012, 875, 866, 804, 737, 698, 569 Mass spectrum (FAB) m/z: 348((M+H)⁺) (acid free form)

EXAMPLE 65(2R)-Amino-2-methyl-4-{5-[3-(4-methylcyclohexyloxy)propynyl]thiophen-2-yl]butan-1-olmaleate (exemplification compound No.1-1050)

[0968] The title compound was obtained according to a similar reactionto that described in Example 1.

[0969] Nuclear magnetic resonance spectrum (400 MHz, CH₃OD) δ ppm: 0.89,0.90 (total 3H, d, J=6.4 Hz), 1.31 (3H, s), 0.92-1.56, 1.70-2.12 (total11H, m), 2.81-2.96 (2H, m), 3.40-3.49, 3.73-3.79 (total 1H, m), 3.52(1H, d, J=11.2 Hz), 3.61 (1H, d, J=11.2 Hz), 4.36, 4.39 (total 2H, s),6.25 (2H, s), 6.78 (1H, d, J=3.6 Hz), 7.04 (1H, d, J=3.6 Hz) Infraredabsorption spectrum ν_(max) cm⁻¹ (KBr): 2927, 2864, 2219, 1579, 1508,1386, 1366, 1193, 1093, 1077, 876, 865, 807, 717, 568 Mass spectrum(FAB) m/z: 336 ((M+H)⁺) (acid free form)

EXAMPLE 66 (4R)-Methyl-4-[2-(thiophen-2-yl)ethyl]oxazolidin-2-one(exemplification compound No.4-4) EXAMPLE 66(a)(2R)-t-Butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol

[0970] 2-t-Butoxycarbonylamino-2-methyl-1,3-propanediol (20.0 g, 97.4mmol) was suspended in diisopropyl ether (200 ml), and n-hexanoic acidvinyl ester (16.3 ml, 0.10 mmol) and lipase [Immobilized lipase fromPseudomonas sp. (TOYOBO; 0.67 U/mg)] (0.8 g) were added thereto followedby stirring vigorously for 2 hours at room temperature. The reactionsolution was filtered, and the filtrate was evaporated under reducedpressure. The obtained residue was purified by chromatography on asilica gel column (elution solvent; hexane:ethyl acetate=10:1−2:1) toafford the title compound (25.0 g, 85% yield) as a colorless oil.

[0971] The obtained(2R)-t-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol wassubjected to an optically active HPLC column for analytical separation(ChiralCel OF (Daisel), 0.46 cm×25 cm, elution solvent;n-hexane:2-propanol=70:30, flow rate; 0.5 ml/mm) to determine theoptical purity.

[0972] The peaks of the former elution band (8.2 mm) and the latter one(10.5 mm) corresponded to the 2S form and 2R form, respectively. Theoptical purity of this reaction product was confirmed to be 85% ee.

[0973] [α]_(D) ²⁵ −8.5 (c 1.86°, CHCl₃) Nuclear magnetic resonancespectrum (400 MHz, CDCl₃) δ ppm: 4.86 (s, 1H), 4.25 (d, 1H, J=11.2 Hz),4.19 (d, 1H, J=11.2 Hz), 3.86 (brs, 1H), 3.70-3.55 (m, 2H), 2.36 (t, 2H,J=7.4 Hz), 1.68-1.58 (m, 2H), 1.44 (s, 9H), 1.40-1.30 (m, 4H), 1.25 (s,3H), 0.90 (t, 3H, J=7.0 Hz) Infrared absorption spectrum ν_(max) cm⁻¹(KBr): 3415, 3380, 2961, 2935, 2874, 1721, 1505, 1458, 1392, 1368, 1293,1248, 1168, 1076 Mass spectrum (FAB) m/z: 304 ((M+H)⁺)

EXAMPLE 66(b)(2S)-t-Butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanal

[0974] (2R)-t-Butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol(30.7 g, 0.10 mol) obtained in Example 66(a) was dissolved indichloromethane (600 ml), and then molecular sieve 4 Å (220 g) andpyridinium chlorochromate (43.6 g, 0.20 mol) were added thereto in anice bath followed by stirring for 2 hours at room temperature. Thereaction solution was diluted with ether, and then the solution wasfiltered. The-filtrate was evaporated in vacuo, and the residue waspurified by chromatography on a silica gel column (elution solvent;n-hexane:ethl acetate=10:1−5:1) to give the title compound (28.8 g, 95%yield) as a colorless oil.

[0975] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 9.45(s, 1H), 5.26 (brs, 1H), 4.44 (d, 1H, J=11.2 Hz), 4.32 (d, 1H, J=11.2Hz), 2.32 (t, 2H, J=7.6 Hz), 1.70-1.55 (m, 2H), 1.45 (s, 9H), 1.38 (s,3H), 1.40-1.25 (m, 4H), 0.90 (t, 3H, J=7.0 Hz) Infrared absorptionspectrum ν_(max) cm⁻¹ (liquid film): 3367, 2961, 2935, 2874, 1742, 1707,1509, 1458, 1392, 1369, 1290, 1274, 1254, 1166, 1100, 1078 Mass spectrum(FAB) m/z: 302 ((M+H)⁺)

EXAMPLE 66(c)(2R)-t-Butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4-(thiophen-2-yl)-3-butene

[0976] 2-Thienylmethyltriphenylphosphonium bromide (67.1 g, 0.15 mol)was suspended in tetrahydrofuran (750 ml), and potassium t-butoxide(17.2 g, 0.15 mol) was added thereto followed by stirring under anitrogen atmosphere for 20 minutes at room temperature. Atetrahydrofuran (250 ml) solution of(2S)-t-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanal (23.0 g,76.4 mmol) obtained in Example 66(b) was added dropwise to the reactionsolution in an ice bath, and then the reaction mixture was stirred for30 minutes in the ice bath. To the reaction solution was added water,and the resulting solution was extracted with ethyl acetate, and thenthe ethyl acetate layer was washed with a saturated aqueous sodiumchloride solution. The ethyl acetate layer was dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by chromatography on a silica gel column(elution solvent; n-hexane:ethyl acetate=20:1) to afford the titlecompound (27.8 g, 96% yield) as a colorless oil.

[0977] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:7.32-7.26, 7.16-7.14 (m, total 1H), 7.04-7.01, 7.01-6.93 (m, total 2H),6.63 (d, 0.5 H, J=16.0 Hz), 6.60 (d, 0.5 H, J=13.6 Hz), 6.10 (d, 0.5 H,J=16.0 Hz), 5.58 (d, 0.5 H, J=13.6 Hz), 4.94, 4.93 (brs, total 1H),4.40-4.10 (m, 2H), 2.34 (t, 2H, J=7.4 Hz), 1.70-1.55 (m, 2H), 1.57,1.50, 1.44 (s, total 9H), 1.40-1.25 (m, 7H), 0.88 (t, 3H, J=7.0 Hz)Infrared absorption spectrum ν_(max) cm⁻¹ (liquid film): 3370, 2961,2933, 1725, 1495, 1456, 1391, 1367, 1247, 1167, 1109, 1100, 1072, 697Mass spectrum (FAB) m/z: 381 (M⁺)

EXAMPLE 66(d) (4R)-Methyl-4-[2-(thiophen-2-yl)ethenyl]oxazolidin-2-one

[0978](2R)-t-Butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4-(thiophen-2-yl)-3-butene(40.5 g, 0.11 mol) obtained in Example 66(c) was dissolved in themixture of tetrahydrofuran (150 ml) and methanol (150 ml), and a 1Naqueous sodium hydroxide solution (530 ml) was added thereto in an icebath followed by stirring for 30 minutes in the ice bath andsubsequently for 1 hour at room temperature. After the reaction solutionwas concentrated in vacuo, water was added thereto, and the solution wasextracted with dichloromethane, and then the dichloromethane layer waswashed with a saturated aqueous sodium chloride solution. Thedichloromethane layer was dried over anhydrous sodium sulfate, and thesolvent was evaporated in vacuo to give a crude product (35.0 g). Thiscrude product was dissolved in tetrahydrofuran (300 ml), and t-butoxypotassium (17.8 g, 0.16 mol) was added thereto in an ice bath followedby stirring for 10 minutes in the ice bath and subsequently for 40minutes at room temperature. To the reaction solution was added water,and the resulting solution was extracted with ethyl acetate, and thenthe ethyl acetate layer was washed with the saturated aqueous sodiumchloride solution. After the ethyl acetate layer was dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure. The residue was purified by chromatography on a silica gelcolumn (elution solvent; hexane:ethyl acetate=3:1−1:1) to afford thetitle compound (18.0 g, 81% yield) as a white solid.

[0979] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 7.34(d, 0.5H, J=5.1 Hz), 7.19 (d, 0.5H, J=5.0 Hz), 7.07-6.91 (m, 2H), 6.74(d, 0.5H, J=16.0 Hz), 6.59 (d, 0.5H, J=12.5), 6.17 (brs, 1H), 6.06 (d,0.5H, J=16.0 Hz), 5.65 (d, 0.5H, J=12.5 Hz), 4.41 (d, 0.5H, J=8.6 Hz),4.31-4.16 (m, 1.5H), 1.60 (s, 1.5H), 1.55 (s, 1.5H) Infrared absorptionspectrum ν_(max) cm⁻¹ (KBr): 3275, 3110, 2974, 1752, 1391, 1376, 1281,1169, 1039, 960, 704 Mass spectrum (FAB) m/z: 209 (M⁺)

EXAMPLE 66(e) (4R)-Methyl-4-r2-(thiophen-2-yl)ethyl]oxazolidin-2-one

[0980] (4R)-Methyl-4-[2-(thiophen-2-yl)ethenyl]oxazolidin-2-one (18.0 g,86.0 mmol) obtained in Example 66(d) was dissolved in methanol (150 ml),and 10% palladium-charcoal (4.5 g) was added thereto followed bystirring for 10 hours at room temperature under a hydrogen atmosphere.The palladium-charcoal in the reaction solution was removed byfiltration using Kiriyama funnel covered with a silica gel thin layer,and the filtrate was evaporated in vacuo. The obtained solid was washedwith diethyl ether, and dried to give the title compound (16.5 g, 91%yield) as a white solid.

[0981] The obtained(4R)-methyl-4-[2-(thiophen-2-yl)ethyl]oxazolidin-2-one was subjected toan optically active HPLC column for analytical separation (ChiralCelOD-H (Daisel), 0.46 cm×25 cm, elution solvent;n-hexane:2-propanol=60:40, flow rate; 0.5 ml/mm) to determine theoptical purity.

[0982] The peaks of the former elution band (16.8 mm) and the latter one(17.6 mm) corresponded to the 2S form and 2R form, respectively. Theoptical purity of this reaction product was confirmed to be 85% ee.

[0983] [α]D²⁵ +5.1 (c 2.4, CHCl₃) Nuclear magnetic resonance spectrum(400 MHz, CDCl₃) δ ppm: 7.15 (d, 1H, J=5.2 Hz), 6.93 (dd, 1H, J=5.2, 3.6Hz), 6.81 (d, 1H, J=3.6 Hz), 5.39 (brs, 1H), 4.19 (d, 1H, J=8.4 Hz),4.08 (d, 1H, J=8.4 Hz), 3.00-2.84 (m, 2H), 2.08-1.92 (m, 2H), 1.42 (s,3H) Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3283, 1770, 1399,1244, 1043, 941, 846, 775, 706, 691 Mass spectrum (EI) m/z: 211 (M⁺)

[0984] This optical purity 85% ee compound,(4R)-methyl-4-[2-(thiophen-2-yl)ethyl]oxazolidin-2-one (11 g) wasdissolved in a mixture of ethyl acetate (25 ml) and n-hexane (5.0 ml) byheating, and the solution was left at room temperature for 2 hours. Theprecipitated white crystals were filtered off, and dried to give thetitle compound (4.0 g, optical purity 99% ee).

[0985] [α]D²⁵ +7.8 (c 2.0°, CHCl₃)

EXAMPLE 67 (4R)-Methyl-4-[2-(thiophen-2-yl)ethyl]oxazolidin-2-one(exemplification compound No.4-4) EXAMPLE 67(a)(2R)-t-Butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4-(thiophen-2-yl)butane

[0986](2R)-t-Butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4-(thiophen-2-yl)-3-butene(27.6 g, 72.4 mmol) obtained in Example 66(c) was dissolved in ethanol(450 ml), and 10% palladium-charcoal (14.0 g) was added thereto followedby stirring for 4 days at room temperature under a hydrogen atmosphere.After the palladium-charcoal in the reaction solution was filtered outthrough Celite, the filtrate was evaporated to dryness under reducedpressure. The residue was purified by chromatography on a silica gelcolumn (elution solvent; hexane:ethyl acetate=20:1−10:1) to give thetitle compound (22.1 g, 80% yield) as a colorless oil.

[0987] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: :7.02 (d, 1H, J=5.2 Hz), 6.91 (dd, 1H, J=5.2, 3.6 Hz), 6.80 (d, 1H, J=3.6Hz), 4.53 (brs, 1H), 4.26-4.12 (m, 2H), 2.85 (t, 2H, J=8.4 Hz), 2.34 (t,2H, J=7.6 Hz), 2.26-2.16 (m, 1H), 2.01-1.90 (m, 1H), 1.68-1.56 (m, 2H),1.44 (s, 9H), 1.31 (s, 3H), 1.40-1.26 (m, 4H), 0.89 (t, 3H, J=7.6 Hz)Infrared absorption spectrum ν_(max) cm⁻¹ (liquid film): 3371, 2961,2933, 2872, 2864, 1721, 1502, 1466, 1455, 1392, 1367, 1246, 1168, 1074,694 Mass spectrum (FAB) m/z: 384 ((M+H)⁺)

EXAMPLE 67(b)(2R)-t-Butoxycarbonylamino-2-methyl-4-(thiophen-2-yl)-1-butanol

[0988](2R)-t-Butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4-(thiophen-2-yl)butane(22.0 g, 57.4 mmol) obtained in Example 67(a) was dissolved in a mixturesolution of tetrahydrofuran (140 ml) and methanol (280 ml), and a 1Naqueous sodium hydroxide solution (280 ml) was added in an ice bathfollowed by stirring 30 minutes in an ice bath and subsequently for 1hour at room temperature. The reaction solution was concentrated invacuo, and water was added thereto, and after the resulting solution wasextracted with dichloromethane, the dichloromethane layer was washedwith a saturated aqueous sodium chloride solution. The dichloromethanelayer was dried over anhydrous sodium sulfate, and the solvent wasevaporated in vacuo to afford the title compound (15.5 g, 95% yield) asa white solid.

[0989] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: :7.11 (d, 1H, J=5.2 Hz), 6.92 (dd, 1H, J=5.2, 3.6 Hz), 6.81 (d, 1H, J=3.6Hz), 4.64 (brs, 1H), 4.08 (brs, 1H), 3.74-3.60 (m, 2H), 2.98-2.76 (m,2H), 2.20-2.10 (m, 1H), 2.03-1.90 (m, 1H), 1.44 (s, 9H), 1.22 (s, 3H)Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3279, 3250, 3067, 2973,2929, 2908, 2857, 1679, 1552, 1367, 1291, 1245, 1167, 1076, 1064, 1009,861, 851, 701 Mass spectrum (FAB) m/z: 286 ((M+H)⁺)

EXAMPLE 67(c) (4R)-Methyl-4-[2-(thiophen-2-yl)ethyl]oxazolidin-2-one

[0990] (2R)-t-Butoxycarbonylamino-2-methyl-4-(thiophen-2-yl)-1-butanol(15.4 g, 53.9 mmol) obtained in Example 67(b) was dissolved inN,N-dimethylformamide (200 ml), and potassium t-butoxide (9.07 g, 80.8mmol) was added thereto in an ice bath followed by stirring for 10minutes in an ice bath and subsequently for 40 minutes at roomtemperature. To the reaction solution was added water, and then thesolution was extracted with ethyl acetate, and after the ethyl acetatelayer was washed with a saturated aqueous sodium chloride solution,dried over anhydrous sodium sulfate, and the solvent was evaporated invacuo. The residue was purified by chromatography on a silica gel column(elution solvent; hexane:ethyl acetate=3:1−1:1) to afford the titlecompound (11.5 g, 100% yield) as a white solid. The data obtained fromanalytical instruments were in accord with that obtained in Example 66.

EXAMPLE 68(4R)-[2-(benzo[b]thiolphen-6-yl)ethyl]-4-methyloxazolidin-2-one(exemplification compound No.4-17) EXAMPLE 68(a)(2R)-t-Butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4-(benzo[b]thiophen-6-yl)-3-butene

[0991](2R)-t-Butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanal-(28.2 g,93.6 mmol) obtained in Example 66(b) and6-bromotriphenylphosphoniumbenzo[b]thiophene (45.8 g, 93.6 mmol) weresuspended in tetrahydrofuran (700 ml), and potassium t-butoxide (11.6 g,0.10 mol) were added thereto followed by stirring for 30 minutes at roomtemperature. To the resulting reaction solution was added water, and thesolution was extracted with ethyl acetate, and then the ethyl acetatelayer was washed with a saturated aqueous sodium chloride solution. Theethyl acetate layer was dried over anhydrous sodium sulfate, and thesolvent was evaporated in vacuo. The residue was purified bychromatography on a silica gel column (elution solvent; hexane:ethylacetate=10:1) to afford the title compound (28.0 g, 69% yield) as acolorless oil.

[0992] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 7.82(d, 1H, J=9.7 Hz), 7.75 (d, 1H, J=8.2 Hz), 7.44-7.39 (m, 1H), 7.32-7.26(m, 2H), 6.74, 5.73 (d, total 1H, J=12.6 Hz), 6.61, 6.34 (d, total 1H,J=16.2 Hz), 4.87, 4.69 (br s, total 1H), 4.34-4.16, (m, 2H), 2.37-2.32(m, 2H), 1.67-1.15 (m, 20H), 0.91-0.84 (m, 3H). Infrared absorptionspectrum ν_(max) cm⁻¹ (liquid film): 3440, 3373, 2961, 2932, 2872, 1724,1597, 1498, 1457, 1390, 1367, 1247, 1167, 1099, 1073 Mass spectrum (FAB)m/z: 431 (M⁺)

EXAMPLE 68(b)(2R)-t-Butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4-(benzo[b]thiophen-6-yl)butane

[0993](2R)-t-Butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4-(benzo[b]thiophen-6-yl)-3-butene(28.0 g, 64.9 mmol) obtained in Example 68(a) was dissolved in methanol(700 ml), and 10% palladium-charcoal (14.0 g) was added thereto followedby stirring for 6 days at room temperature under a hydrogen atmosphere.After the palladium-charcoal in the reaction solution was filtered outthrough Celite, the filtrate was evaporated under reduced pressure. Theresidue was purified by chromatography on a silica gel column (elutionsolvent; hexane:ethyl acetate=15:1−10:1) to give the title compound(24.30 g, 87% yield) as a colorless oil.

[0994] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 7.73(d, 1H, J=8.2. Hz), 7.69 (s, 1H), 7.36 (d, 1H, J=5.2 Hz), 7.28 (d, 1H,J=5.6 Hz), 7.19 (d, 1H, J=8.1 Hz), 4.56 (br s, 1H), 4.28 (d, 1H, J=11.0Hz), 4.14 (d, 1H, J=11.0 Hz), 2.73 (t, 2H, J=8.7 Hz), 2.34 (t, 2H, J=7.5Hz), 1.68-1.61 (m, 2H), 1.45 (s, 9H), 1.41-1.38 (m, 8H), 0.89 (t, 3H,J=6.7 Hz). Infrared absorption spectrum ν_(max) cm⁻¹ (liquid film):3371, 2960, 2933, 2870, 1720, 1604, 1501, 1466, 1392, 1367, 1248, 1167,1074 Mass spectrum (FAB) m/z: 456 ((M+Na)⁺)

EXAMPLE 68(c)(4R)-[2-(benzo[b]thiophen-6-yl)ethyl]-4-methyloxazolidin-2-one

[0995](2R)-t-Butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4-(benzo[b]thiophen-6-yl)butane(24.3 g, 56.0 mmol) obtained in Example 68(b) was dissolved in a mixtureof tetarahydrofuran (220 ml) and methanol (110 ml), and a 1N aqueoussodium hydroxide solution (110 ml) was added thereto in an ice bathfollowed by stirring for 15 minutes in the ice bath and subsequently for2 hours at room temperature. After the reaction solution wasconcentrated in vacuo, water was added thereto, and the solution wasextracted with dichloromethane, and then the dichloromethane layer waswashed with a saturated aqueous sodium chloride solution. Thedichloromethane layer was dried over anhydrous sodium sulfate, and thesolvent was evaporated in vacuo to give a crude product (i 8.8 g, 100%yield). This crude product was dissolved in dimethylformamide (380 ml),and potassium t-butoxide (9.43 g, 84.1 mmol) was added thereto in an icebath followed by stirring for 5 minutes in the ice bath and subsequentlyfor 1 hour at room temperature. To the reaction solution was addedwater, and the resulting solution was extracted with ethyl acetate, andthen the ethyl acetate layer was washed with a saturated aqueous sodiumchloride solution. After the ethyl acetate layer was dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure. The residue was purified by chromatography on a silica gelcolumn (elution solvent; hexane:ethyl acetate=3:2−2:1) to afford thetitle compound (13.8 g, 94% yield) as a white solid.

[0996] The obtained compound,(4R)-[2-(benzo[b]thiophen-6-yl)ethyl]-4-methyloxazolidin-2-one wassubjected to an optically active HPLC column for analytical separation(ChiralCel AD (Daisel), 0.46 cm×25 cm, elution solvent;n-hexane:2-propanol=70:30, flow rate; 0.5 m/mm) to determine the opticalpurity.

[0997] The peaks of the former elution band (15.9 mm) and the latter one(17.6 mm) corresponded to the 4S form and 4R form, respectively. Theoptical purity of this reaction product was confirmed to be 80% ee.

[0998] [α]_(D) ²⁴ +2.3 (c 0.6, CHCl₃) Nuclear magnetic resonancespectrum (400 MHz, CDCl₃) δ ppm: 7.73 (d, 1H, J=8.2 Hz), 7.68 (s, 1H),7.38 (d, 1H, J=5.7 Hz), 7.29 (d, 1H, J=13.0 Hz), 7.18 (d, 1H, J=13.6Hz), 5.91 (br s, 1H), 4.21 (d, 1H, J=8.7 Hz), 4.09 (d, 1H, J=8.7 Hz),2.84-2.76 (m, 2H), 1.97 (t, J=8.5 Hz, 3H). Infrared absorption spectrumν_(max) cm⁻¹ (KBr): 3292, 2970, 2930, 1749, 1722, 1601, 1479, 1461,1397, 1277, 1045 Mass spectrum (EI) m/z: 261 (M⁺)

EXAMPLE 69(2R)-t-Butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol

[0999] 2-t-Butoxycarbonylamino-2-methyl-1,3-propanediol (200 mg, 0.97mmol) was dissolved in diisopropylether (2 ml), and n-hexanoic acidvinyl ester (0.16 ml, 1.02 mmol) and lipase [Immnobilized lipase fromPseudomonas sp. (TOYOBO; 0.67 U/mg)] (20 mg) were added thereto followedby stirring 4 hours at room temperature. After the insoluble substancesin the reaction mixture were removed by filtration, the filtrate wasconcentrated, and the residue was purified by flash chromatography on asilica gel column (elution solvent; n-hexane:ethyl acetate=10:1−7:3) togive the title compound (258 mg, 87% yield) as a colorless oil. Theobtained compound,(2R)-t-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol wassubjected to an optically active HPLC column for analytical separation(ChiralCel OF (Daisel), 0.46 cmφ×25 cm, elution solvent;n-hexane:2-propanol=70:30, flow rate; 0.5 ml/mm) to determine theoptical purity.

[1000] The peaks of the former elution band (8.2 mm) and the latter one(10.5 mm) corresponded to the 2S form and 2R form, respectively. Theoptical purity in this reaction was confirmed to be 89% ee.

[1001] The absolute configuration of the title compound was determinedby comparison of the specific rotation of the known compound,(2R)-t-butoxycarbonylamino-2-methyl-3-buten-1-ol (Tetrahedron Asymmetry10 (1999) 4653-4661) which can be easily synthesized from the titlecompound as described in Reference example 1(a).

[1002] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:4.89(1H,br.s), 4.24(1H,d,J=11.2 Hz), 4.19(1H,d,J=11.2 Hz),3.66-3.54(2H,m), 2.36(2H,t,J=7.4 Hz), 1.69-1.57(2H,m), 1.44(9H,s),1.39-1.22(4H,m), 1.25(3H,s), 0.90(3H,t,J=6.6Hz) Infrared absorptionspectrum ν_(max) cm⁻¹ (CHCl₃): 3411, 3380, 2961, 2934, 1722, 1504, 1459,1392, 1368, 1292, 1248, 1168, 1077, 1015 Optical rotation [α]_(D) ²⁴:−1.1° (c =0.81, methanol)

EXAMPLE 70 (2R)-t-Butoxycarbonylamino-3-n-hexanoyloxy-2-ethyl-1-propanol

[1003] The title compound was obtained as a colorless oil (252 mg, 87%yield) according to a similar reaction to that described in Example 69using 2-t-butoxycarbonylamino-2-ethyl-1,3-propanediol (200 mg, 0.91mmol).

[1004] The obtained compound,(2R)-t-butoxycarbonylamino-3-n-hexanoyloxy-2-ethyl-1-propanol wassubjected to an optically active HPLC column for analytical separation(ChiralCel OF (Daisel), 0.46 cmφ×25 cm, elution solvent;n-hexane:2-propanol=70:30, flow rate; 0.5 ml/mm) to determine theoptical purity.

[1005] The peaks of the former elution band (8.5 mm) and the latter one(10.7 mm) corresponded to the 2S form and 2R form, respectively. Theoptical purity in this reaction was confirmed to be 95% ee.

[1006] The absolute configuration of the title compound was determinedby comparison of the specific rotation of the known compound,(+)-(R)-α-ethyl-α-vinylglycine (Helvetica Chimica Acta 69 (1986)1365-1377) which can be easily synthesized from the-title compound asdescribed in Reference example 5(f).

[1007] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:4.78(1H,br.s), 4.28(1H,d,J=11.1 Hz), 4.13(1H,d,J=11.1 Hz),3.72-3.57(2H,m), 2.35(2H,t,J=7.6 Hz), 1.83-1.54(4H,m), 1.44(9H,s),1.38-1.24(4H,m), 0.95-0.86(6H,m) Infrared absorption spectrum ν_(max)cm⁻¹ (CHCl₃): 3371, 2966, 2935, 1722, 1503, 1460, 1368, 1249, 1168,1086, 1028, 866, 781 Optical rotation [α]_(D) ²⁴: −2.4° (c=0.72,methanol)

[1008] The known and useful compounds, (−)-(R)-α-methyl-α-vinylglycine(Reference example 1), (+)-(S)-α-methyl-α-ethylglycine (Referenceexample 2), and (+)-(R)-α-ethyl-α-vinylglycine (Reference example 3)were prepared by using the compounds obtained in Example 69 or Example70.

REFERENCE EXAMPLE 1 (−)-(R)-α-Methyl-α-vinylglycine REFERENCE EXAMPLE1(a) (2R)-t-Butoxycarbonylamino-2-methyl-3-buten-1-ol

[1009] To the dichloromethane solution (18 ml) of(2R)-t-buthoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol (1.5 g,4.9 mmol) obatained in Example 69 was added molecular sieve 4 Å (10.5 g)thereto, and after stirring for 10 minutes at room temperature,pyridinium chlorochromate (2.1 g, 9.8 mmol) were added thereto followedby stirring for 1 hours.

[1010] To the reaction solution was added diethyl ether, and insolublesubstances of the solution were filtered out by a silica gel shortcolumn (elution solvent:diethyl ether). The organic solvents of thefiltrate were evaporated in vacuo, and the obtained residue (1.5 g) wasused for the following reaction.

[1011] To a suspension of methyltriphenylphosphonium bromide (4.5 g,12.5 mmol) in tetrahydrofuran (10 ml) was added potassium t-butoxide(1.3 g, 1.1.5 mmol) at 0° C. followed by stirring for 1 hour. To thisreaction solution was added dropwise a tetrahydrofuran solution (10 ml)of the residue obtained in the previous reaction. After this reactionmixture was stirred for 30 minutes at 0° C., distilled water was addedthereto followed by extraction with ethyl acetate. The ethyl acetatelayer was washed with distilled water and subsequently with a saturatedaqueous sodium chloride solution, and dried over magnesium sulfate.After the solvent was evaporated, the insoluble substances were filteredout by a silica gel short column (elution solvent: hexane:ethylacetate=10:1). The filtrate was concentrated, and the obtained residue(1.2 g) was dissolved in methanol (20 ml), and then a 1N aqueous sodiumhydroxide solution (20 ml) was added thereto followed by stirring for 30minutes at room temperature. After, to this reaction solution was addeddiethyl ether, the solution was washed with distilled water andsubsequently with the saturated aqueous sodium chloride solution, anddried over magnesium sulfate. The solvent was evaporated, and theresidue was purified by preparative thin layer chromatography (elutionsolvent; hexane:ethyl acetate=1:1) to give the title compound (180 mg,0.894 mmol, 18% yield).

[1012] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:5.89(1H,ddd,J=11.0,6.6,1.5 Hz), 5.21(1H,d,J=1.5 Hz), 5.17(1H,d,J=6.6Hz), 4.84(1H,br.s), 3.76(1H,br.s), 3.62(2H,m), 1.44(9H,s), 1.32(3H,s)Infrared absorption spectrum ν_(max) cm⁻¹ (CHCl₃): 3418, 3348, 2979,1692, 1499, 1455, 1393, 1368, 1283, 1253, 1170, 1074, 918 Opticalrotation [α]_(D) ²⁴: +10.4° (c=0.51, methanol)

REFERENCE EXAMPLE 1(b) (2R)-t-Butoxycarbonylamino-2-methyl-3-butenal

[1013] (2R)-t-Butoxycarbonylamino-2-methyl-3-buten-1-ol (180 mg, 0.894mmol) obtained in Reference example 1(a) was dissolved indichloromethane (5.0 ml), and molecular sieve 4 Å (2.0 g) and pyridiniumchlorochromate (386 mg, 1.79 mmol) were added thereto in an ice bathfollowed by stirring for 1 hour at room temperature. To the reactionsolution was added ether, and insoluble substances of the solution werefiltered out, and then the filtrate was evaporated in vacuo. The residuewas purified by flash chromatography on a silica gel column (elutionsolvent; n-hexane:ethyl acetate=10:1) to give the title compound (160mg, 90% yield) as a colorless oil.

[1014] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:9.26(1H,s), 5.83(1H,dd,J=17.5,10.6 Hz), 5.35(1H,d,J=10.6 Hz),5.32(1H,d,J=17.5 Hz), 5.22(1H,br.s), 1.48(3H,s), 1.45(9H,s) Infraredabsorption spectrum ν_(max) cm⁻¹ (CHCl₃): 3350, 2980, 1737, 1707, 1505,1455, 1369, 1279, 1256, 1168, 1069, 925, 867

REFERENCE EXAMPLE 1(c) (2R)-t-Butoxycarbonylamino-2-methyl-3-butenoicacid

[1015] (2R)-t-Butoxycarbonylamino-2-methyl-3-butenal (160 mg, 0.803mmol) obtained in Reference example 1(b) was dissolved in a mixture oft-butanol (8.0 ml) and water (2.0 ml), and then 2-methyl-2-butene (0.38ml, 3.61 mmol), sodium dihydrogenphosphate dihydrate (96 mg, 0.803mmol), and sodium chlorite (254 mg, 2.81 mmol) were added theretofollowed by stirring 1 hour at room temperature. To the reactionsolution was added ethyl acetate, and the ethyl acetate layer was washedwith a saturated aqueous sodium chloride solution. The ethyl acetatelayer was dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by flashchromatography on a silica gel column (elution solvent; n-hexane:ethylacetate=20:1−1:1) to give the title compound (130 mg, 75% yield) as acolorless oil.

[1016] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:5.07(1H,br.s), 5.68(1H,br.s), 5.12(1H,d,J=17.4 Hz), 5.05(1H,d,J=10.6Hz), 1.48(3H,s), 1.40(9H,s) Infrared absorption spectrum ν_(max) cm⁻¹(CHCl₃): 3394, 2980, 1691, 1602, 1483, 1455, 1368, 1253, 1172, 1066, 756

REFERENCE EXAMPLE 1(d) (−)-(R)-α-Methyl-α-vinylglycine hydrochloride

[1017] (2R)-t-Butoxycarbonylamino-2-methyl-3-butenoic acid (120 mg,0.557 mmol) obtained in Reference example 1(c) was dissolved in ethanol(1.5 ml), and a dioxane solution (1.5 ml) of 4N hydrochloric acid wasadded thereto followed by stirring 18 hours at room temperature. Thereaction solution was concentrated in vacuo, and the residue was washedwith ether, and dried to give the title compound (72 mg, 85% yield) as awhite solid.

[1018] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:6.07(1H,dd,J=17.6,11.0 Hz), 5.48(1H,d,J=11.1 Hz), 5.47(1H,d,J=17.6 Hz),1.66(3H,s) Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3349, 3029,1751, 1524, 1200, 954 Optical rotation [α]_(D) ²⁵: −18.7° (c=0.70, H₂O)

REFERENCE EXAMPLE 1(e) (−)-(R)-α-methyl-α-vinylglycine

[1019] (−)-(R)-α-methyl-α-vinylglycine hydrochloride (60 mg, 0.40 mmol)obtained in Reference example 1(d) was dissolved in ethanol (1.5 ml),and propylene oxide (1.5 ml) was added thereto followed by heating underreflux for 2 hours. The white solid in the reaction solution wasfiltered off to give the title compound (32 mg, 70 % yield) as a whitesolid.

[1020] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:6.17(1H,dd,J=17.2,10.6 Hz), 5.56(1H,d,J=10.6 Hz), 5.54(1H,d,J=17.2 Hz),1.43(3H,s) Infrared absorption spectrum ν_(max) cm⁻¹ (KBr): 3600-2500,1605, 1535, 1455, 1415, 1385, 1360, 1280, 1235, 1150, 1000, 940 Opticalrotation [α]_(D) ²⁵: −27.6° (c=0.62, H₂O)

REFERENCE EXAMPLE 2 (+)-(S)-α-Methyl-α-ethynyl glycine REFERENCE EXAMPLE2(a)3-t-Butoxycarbonyl-2,2-dimethyl-(4R)-n-hexanoyloxymethyl-4-methyloxazolidine

[1021] (2R)-t-Butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-i-propanol(10.1 g, 33.3 mmol) obtained in Example 69 was dissolved indichloromethane (152 ml), and acetone dimethylacetal (16.4 ml, 133 mmol)and p-toluenesulfonic acid (172 mg, 1.00 mmol) were added theretofollowed by stirring 12 hours at room temperature. The reaction solutionwas concentrated, and the residue was purified by flash chromatographyon a silica gel column (elution solvent; n-hexane:ethyl acetate=10:1) toafford the title compound (5.72 g, 50% yield) as a colorless oil.

[1022] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:4.29(1H,s), 4.18(1H,s), 3.99(1H,m), 3.64(1H,m), 2.28-2.34(2H,m),1.26-1.25(24H,m), 0.89(3H,t) Optical rotation [α]_(D) ²⁵: +17.2°(c=1.50, CHCl₃)

REFERENCE EXAMPLE 2(b) 3-t-Butoxycarbonyl-22-dimethyl-(4S)-hydroxymethyl-4-methyloxazolidine

[1023] 3-t-Butoxycarbonyl-2,2-dimethyl-(4R)-n-hexanoyloxymethyl-4-methyloxazolidine (13.7 g, 39.9mmol) obtained in Reference example 2(a) was dissolved indichloromethane (200 ml), and the hexane solution of 1.0Mdiisobutylaluminium hydride (99 ml, 99.7 mmol) was added dropwisethereto at −78° C. After, the reaction mixture was stirred for 30minutes at −78° C., cooled down to room temperature, and 10 wt % aqueouspotassium sodium tartrate solution (200 ml) was added thereto followedby stirring vigorously for 30 minutes. The reaction solution wasextracted with diethyl ether, and after the ether layer was dried overanhydrous sodium sulfate, the solvent was evaporated in vacuo. Theresidue was purified by flash chromatography on a silica gel column(elution solvent; n-hexane:ethyl acetate=5:2) to afford the titlecompound (10.5 g, 100% yield) as a white crystalline solid.

[1024] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:4.49(1H,br.s), 3.55-3.71(4H,m), 1.56(3H,s), 1.49(12H,s), 1.42(3H,s)Optical rotation [α]_(D) ²⁵: −1.67° (c=1.45, CHCl₃)

REFERENCE EXAMPLE 2(c)3-t-Butoxycarbonyl-2,2-dimethyl-(4R)-formyl-4-methyloxazolidine

[1025] 3-t-Butoxycarbonyl-2,2-dimethyl-(4S)-hydroxymethyl-4-methyloxazolidine (9.79 g, 39.9 mmol)obtained in Reference example 2(b) was dissolved in dichloromethane (150ml), and then pyridinium chlorochromate (13.0 g, 59.8 mmol) andmolecular sieve 4 Å (65.0 g) were added thereto in an ice bath followedby stirring for 1 hour at room temperature. The reaction solution wasdiluted with ether, and then the solution was filtered by silica gelcolumn. The filtrate was evaporated in vacuo, and the residue waspurified by flash chromatography on a silica gel column (elutionsolvent; n-hexane:ethyl acetate=8:1) to give the title compound (8.07 g,88% yield) as a white crystalline solid.

[1026] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:9.40-9.48(1H,s), 3.91(1H,d,J=9.2 Hz), 3.67(1H,d,J=9.2 Hz),1.14-1.66(18H,m) Optical rotation [α]_(D) ²⁵: +20.6° (c=1.25, CHCl₃)

REFERENCE EXAMPLE 2(d) 3-t-Butoxycarbonyl-2,2-dimethyl-(4S)-(2,2-dibromo)ethenyl-4-methyloxazolidine

[1027] Triphenylphosphine (17.3 g, 65.8 mmol) was dissolved indichloromethane (25 ml), and a solution of carbon tetrabromide (10.9 g,32.9 mmol) in dichloromethane (15 ml) was added dropwise thereto in anice bath followed by stirring for 5 minutes in the ice bath. To thereaction solution was added dropwise a dichloromethane (40 ml) solutionof 3-t-butoxycarbonyl-2,2-dimethyl-(4S)-formyl-4-methyloxazolidine (4.00g, 16.4 mmol) obtained in Reference example 2(c). After stirring for 14hours at room temperature, insoluble substances of the reaction mixturewere filtered out, the filtrate was concentrated under reduced pressureto give the crude title compound (4.70 g, 71.2% yield) as a colorlessoil.

REFERENCE EXAMPLE 2(e)3-t-Butoxycarbonyl-2,2-dimethyl-(4S)-ethynyl-4-methyloxazolidine

[1028]3-t-Butoxycarbonyl-2,2-dimethyl-(4S)-(2,2-dibromo)ethenyl-4-methyloxazolidine(4.70 g, 11.8 mmol) obtained in Reference example 2(d) was dissolved intetrahydrofuran (94 ml), and n-butyllithium (1.6N hexane solution) wasadded dropwise with stirring at −78° C. followed by stirring for 3.5hours at −78° C. To the reaction solution was added a saturated aqueousammonium chloride solution, and the resulting solution was extractedwith ethyl acetate. The ethyl acetate layer was dried over anhydroussodium sulfate, evaporated in vacuo, and the residue was purified byflash chromatography on a silica gel column (elution solvent;n-hexane:ethyl acetate=15:1) to afford the title compound (2.21 g, 78%yield) as a white crystal.

[1029] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:4.13(1H,d,J=8.4 Hz), 3.84(1H,d,J=8.4 Hz), 2.32(1H,s), 1.49-1.69(18H,m)Optical rotation [α]_(D) ²⁵: +65.6° (c=1.10, CHCl₃)

REFERENCE EXAMPLE 2(f) (2S)-Amino-2-methyl-3-butyn-1-ol

[1030] To3-t-butoxycarbonyl-2,2-dimethyl-(4S)-ethynyl-4-methyloxazolidine (350mg, 1.46 mmol) obtained in Reference example 2(e) was added hydrochloricacid (10 ml), and the solution was stirred for 2 hours at roomtemperature, and then the reaction solution was concentrated to give thecrude title compound (127 mg) as a yellow oil.

REFERENCE EXAMPLE 2(g) (2S)-t-Butoxycarbonyl amino-2-methyl-3-butyn-1-ol

[1031] (2S)-Amino-2-methyl-3-butyn-1-ol (127 mg, 1.28 mmol) obtained inReference example 2(f) was dissolved in a mixture of water (1 ml) andtetrahydrofuran (5 ml), and di-t-butyl dicarbonate (380 mg, 1.74 mmol)and anhydrous sodium carbonate (385 mg, 3.63 mmol) were added theretofollowed by stirring for 14 hours at room temperature. To the reactionsolution was added a saturated aqueous ammonium chloride solution (6ml), and the resulting solution was extracted with ethyl acetate, andthe ethyl acetate layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column (elution solvent; n-hexane:ethylacetate=1:1) to give the title compound (154 mg, 53% yield) as a whitecrystal.

[1032] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:5.00(1H,br.s), 3.78(1H,dd,J=6.0 and 11.2 Hz), 3.67(1H,dd,J=7.9 and 11.2Hz), 3.20(1H,br.s), 2.40(1H,s),1.55(3H,s), 1.46(9H,s) Optical rotation[α]_(D) ²⁵: +1.89° (c=0.70, CHCl₃)

REFERENCE EXAMPLE 2(h) (2S)-t-Butoxycarbonylamino-2-methyl-3-butynicacid

[1033] (2S)-t-Butoxycarbonylamino-2-methyl-3-butyn-1-ol (1.20 g, 6.02mmol) obtained in Reference example 2(g) was dissolved in acetone (30ml), and Jones reagent (3.48 ml, 9.03 mmol) was added thereto followedby stirring for 2 hours in an ice bath. To this reaction solution wasadded more Jones reagent (3.48 ml, 9.03 mmol) followed by stirring for14 hours at room temperature. To the resulting reaction solution wereadded 2-propanol (5 ml) and water (30 ml), and then the solution wasextracted with ethyl acetate. The ethyl acetate layer was dried overanhydrous sodium sulfate, and then the solvent was evaporated in vacuoto give the crude title compound (1.38 g) as a yellow oil.

REFERENCE EXAMPLE 2(i) (+)-(S)-α-Methyl-α-ethynyl glycine hydrochloride

[1034] (2S)-t-Butoxycarbonylamino-2-methyl-3-butynic acid (1.38 g, 6.02mmol) obtained in Reference example 2(h) was dissolved intetrahydrofuran (20 ml), and hydrochloric acid (10 ml) was added theretofollowed by stirring for 5 hours at room temperature. The reactionsolution was concentrated in vacuo, and water (20 ml) and ethyl acetate(10 ml) were added thereto, and then the water layer was concentrated toafford the crude title compound (0.24 g, 27% yield) as a yellowcrystalline solid.

REFERENCE EXAMPLE 2(j) (+)-(S)-α-Methyl-α-ethynylglycine

[1035] To (+)-(S)-α-Methyl-α-ethynylglycine hydrochloride (0.24 g, 6.02mmol) obtained in Reference example 2(i) were added ethanol (9 ml) andpropylene oxide (3 ml) followed by heating under reflux for 2 hours. Thesolid substance obtained by filtration of the reaction solution waswashed with ether to afford the title compound (108 mg, 60% yield) as awhite crystal.

[1036] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:3.06(1H,s), 1.77(3H,s) Optical rotation [α]_(D) ²⁵: +41.7° (c=0.96, H₂O)

REFERENCE EXAMPLE 3 (+)-(R)-α-Ethyl-α-vinyl glycine REFERENCE EXAMPLE3(a) (2S)-t-Butoxycarbonylamino-2-ethyl-3-n-hexanoyloxy-1-propanal

[1037] (2R)-t-Butoxycarbonylamino-3-n-hexanoyloxy-2-ethyl-1-propanol (3g, 9.45 mmol) was dissolved in dichloromethane (60 ml), and thenmolecular sieve 4 Å (20 g) and pyridinium chlorochromate (4.07 g, 18.9mmol) were added thereto in an ice bath followed by stirring for 1 hourat room temperature. The reaction solution was diluted with ether, andafter insoluble substances of the reaction mixture were filtered out,the filtrate was evaporated in vacuo, and then the residue was purifiedby flash chromatography on a silica gel column (elution solvent;n-hexane:ethyl acetate=10:1) to give the title compound (2.79 g, 94%yield) as a colorless oil.

[1038] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:9.34(1H,s), 5.29(1H,br.s), 4.60(1H,d,J=11.5 Hz), 4.40(1H,d,J=11.5 Hz),2.28(2H,t,J=7.5 Hz), 2.05-2.20(1H,m), 1.70-1.80(1H,m), 1.55-1.65(2H,m),1.45(9H,s), 1.25-1.40(4H,m), 0.90(3H,t,J=7.0 Hz), 0.81(3H,t,J=7.5 Hz)Infrared absorption spectrum ν_(max) cm⁻¹ (CHCl₃): 3418, 2979, 2934,2873, 1737, 1710, 1496, 1369, 1251, 1160 Mass spectrum (FAB) m/z: 316((M+H)⁺)

REFERENCE EXAMPLE 3(b)(2R)-t-Butoxycarbonylamino-2-ethyl-3-buten-1-ol-n-hexanoic acid ester

[1039] Methyltriphenylphosphonium bromide (7.90 g, 22.0 mmol) wassuspended in tetrahydrofuran (25 ml), and potassium t-butoxide (2.28 g,20.3 mmol) was added thereto in an ice bath followed by stirring under anitrogen atmosphere.

[1040] (2S)-t-Butoxycarbonylamino-2-ethyl-3-n-hexanoyloxy-1-propanal(2.79 g, 8.85 mmol) obtained in Reference example 3(a) was dissolved intetrahydrofuran (25 ml), and this solution was added dropwise to theprevious reaction solution followed by stirring for 15 minutes. To theresulting mixture solution was added water, and the solution wasextracted, and after ethyl acetate layer was washed with a saturatedaqueous sodium chloride solution, dried on anhydrous magnesium sulfate,and the solvent was evaporated. The residue was purified by flashchromatography on a silica gel column (elution solvent; n-hexane:ethylacetate=40:1−20:1) to give the title compound (1.30 g, 47% yield) as acolorless oil,

[1041] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:5.78(1H,dd,J=17.6,11.0 Hz), 5.22(1H,d,J=11.0 Hz), 5.12(1H,d,J=17.6 Hz),4.62(1H,br.s), 4.29(2H,s), 2.31(2H,t,J=7.5 Hz), 1.83-1.95(1H,m),1.55-1.75(3H,m), 1.44(9H,s), 1.25-1.35(4H,m), 0.83-0.93(6H,m) Infraredabsorption spectrum ν_(max) cm⁻¹ (CHCl₃): 3448, 2972, 2934, 2873, 1721,1494, 1368, 1249, 1163 Mass spectrum (FAB) m/z: 314 ((M+H)⁺)

REFERENCE EXAMPLE 3(c) (2R)-t-Butoxycarbonylamino-2-ethyl-3-buten-1-ol

[1042] (2R)-t-Butoxycarbonylamino-2-ethyl-3-buten-1-ol-n-hexanoic acidester (1.30 g, 4.15 mmol) obtained in Reference example 3(b) wasdissolved in methanol (20 ml), and a 1N aqueous sodium hydroxidesolution (40 ml) was added thereto in an ice bath followed by stirringfor 2 hours at room temperature. To the resulting mixture solution wasadded water, and the solution was extracted with ether, and after etherlayer was washed with a saturated aqueous sodium chloride solution,dried on anhydrous magnesium sulfate, and then the solvent wasevaporated in vacuo. The residue was purified by flash chromatography ona silica gel column (elution solvent; n-hexane:ethyl acetate=9:1−4:1) togive the title compound (0.85 g, 95% yield) as a white solid.

[1043] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:5.77(1H,dd,J=17.0,10.7 Hz), 5.25(1H,d,J=10.7 Hz), 5.16(1H,d,J=17.0 Hz),4.77(1H,br.s), 4.10(1H,br.s), 3.65-3.75(2H,m), 1.58-1.83(2H,m),1.45(9H,s), 0.87(3H,t,J=7.5 Hz) Infrared absorption spectrum ν_(max)cm⁻¹ (CHCl₃): 3348, 3275, 2987, 2969, 2935, 1685, 1541, 1277, 1170, 1053Mass spectrum,(FAB) m/z: 216 ((M+H)⁺) Optical rotation [α]_(D) ²⁴: +2.8°(c=1.03, methanol)

REFERENCE EXAMPLE 3(d) (2R)-t-Butoxycarbonylamino-2-ethyl-3-butenal

[1044] The title compound was obtained as a white solid (0.63 g, 80%yield) according to a similar reaction to that described in Referenceexample 3(a) using (2R)-t-butoxycarbonylamino-2-ethyl-3-buten-1-ol (0.79g, 3.67 mmol) obtained in Reference example 3(c).

[1045] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 9.24(1H,s),5.83(1H,dd,J=17.5,10.7 Hz), 5.39(1H,d,J=10.7 Hz), 5.31(1H,d,J=17.5Hz), 5.29(1H,br.s), 1.85-2.15(2H,m), 1.57(9H,s), 0.85(3H,t,J=7.5 Hz)Infrared absorption spectrum ν_(max) cm⁻¹ (CHCl₃): 3343, 3416, 2980,1712, 1489, 1369, 1249, 1162 Mass spectrum (FAB) m/z: 214 ((M+H)⁺)Optical rotation [α]_(D) ²⁵: +69° (c=1.00, methanol)

REFERENCE EXAMPLE 3(e) (2R)-t-Butoxycarbonylamino-2-ethyl-3-butenoicacid

[1046] (2R)-t-Butoxycarbonylamino-2-ethyl-3-butenal (0.60 g, 2.81 mmol)obtained in Reference example 3(d) was dissolved in the mixture oft-butanol (8 ml) and water (2 ml), and 2-methyl-2-butene (1.34 ml, 12.7mmol), sodium dihydrogenphosphate dihydrate (0.44 g, 2.81 mmol), andsodium chlorite (0.89 g, 9.85 mmol) were added thereto followed bystirring 1 hour at room temperature. To the reaction solution was addedethyl acetate, and the ethyl acetate layer was washed with a saturatedaqueous sodium chloride solution. The ethyl acetate layer was dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by flash chromatography on asilica gel column (elution solvent; n-hexane:ethyl acetate=20:1−1:1) togive the title compound (0.42 g, 65% yield) as a white solid.

[1047] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:6.05(1H,dd,J=17.3,10.7 Hz), 5.25-5.35(3H,m), 1.95-2.20(2H,m),1.44(9H,s), 0.90(3H,t,J=7.4 Hz) Infrared absorption spectrum ν_(max)cm⁻¹ (CHCl₃): 3430, 2981, 1713, 1493, 1369, 1252, 1166 Mass spectrum(FAB) m/z: 230 ((M+H)⁺) Optical rotation [α]_(D) ²⁵: +19.4° (c=1.00,methanol)

REFERENCE EXAMPLE 3(f) (+)-(R)-α-Ethyl-α-vinylglycine

[1048] (2R)-t-Butoxycarbonylamino-2-ethyl-3-butenoic acid (379 mg, 1.65mmol) obtained in Reference example 3(e) was dissolved in ethanol (2ml), and a dioxane solution (2 ml) of 4N hydrochloric acid was addedthereto followed by stirring for 18 hours at room temperature. Thereaction solution was concentrated under reduced pressure, and then theresidue was washed with ether and dried. The obtained white solid wasdissolved in ethanol (6 ml), and propylene oxide (2 ml) was addedthereto followed by heating under reflux. The title compound (83 mg) wasobtained as a white solid by filtering off the white solid in thereaction solution. After the filtrate was concentrated, the residue wasdissolved in water, and the solution was filtered through Bond Elut HF(C₁₈), and then the filtrate was concentrated to give the title compound(61 mg, total amount 144 mg, 75% yield).

[1049] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:6.08(1H,dd,J=17.7,11.1 Hz), 5.41(1H,d,J=11.1 Hz), 5.34(1H,d,J=17.7 Hz),1.82-2.12(2H,m), 0.95(3H,t,J=7.6 Hz) Infrared absorption spectrumν_(max) cm⁻¹ (KBr): 3200-2400, 1623, 1605, 1511, 1369 Mass spectrum(FAB) m/z: 130 ((M+H)⁺) Optical rotation [α]_(D) ²⁵: +20.6° (c=1.00,H₂O)

REFERENCE EXAMPLE 4 5-(4-Fluorophenyl)pent-1-yne

[1050] Sodium hydride (2.11 g, 48.4 mmol) was suspended in anhydroustetrahydrofuran (60 ml), and diethylphosphonoacetic acid ethyl ester(10.84 g, 48.4 mmol) was added dropwise thereto in an ice bath followedby stirring for 10 minutes. To this mixture solution, a solution of4-fluorobenzaldehyde (5.00 g, 40.3 mmol) in anhydrous tetrahydrofuran(60 ml) was added dropwise at the same temperature. The reactionsolution was stirred for 3 hours, and poured into ice-cold water (150ml), and then extracted with ethyl acetate. The organic layer was driedover magnesium sulfate, and the solvent was evaporated in vacuo, andthen the residue was purified by flash chromatography on a silica gelcolumn (elution solvent; hexane:ethyl acetate=10:1−3:1) to give4-fluorocinnamic acid ethyl ester (6.69 g, 86% yield) as a colorlessoil.

[1051] This ester (6.52 g, 33.6 mmol) was dissolved in ethyl acetate(100 ml), and 5% rhodium/alumina (1.30 g) was added thereto followed bystirring under a hydrogen atmosphere for 8 hours at room temperature.The reaction mixture was filtered through Celite, and the filtrate wasconcentrated under reduced pressure, and then the residue was dissolvedin anhydrous tetrahydrofuran (30 ml). This solution was added dropwiseto a suspension of lithium aluminium hydride (1.26 g, 33.2 mmol) inanhydrous tetrahydrofuran (60 ml) in the ice bath. The reaction mixturewas stirred for 30 minutes at the same temperature, and a saturatedaqueous sodium sulfate solution was added thereto followed by stirringfor 10 minutes at room temperature. The mixture was filtered throughCelite, and the filtrate was extracted with ethyl acetate. The organiclayer was washed with a saturated aqueous sodium chloride solution, anddried over anhydrous magnesium sulfate. The solvent was evaporated invacuo, and the residue was purified by flash chromatography on a silicagel column (elution solvent; hexane:ethyl acetate=5:1−1:1) to give4-fluorophenylpropan-1-ol (4.86 g, 95% yield) as a colorless oil.

[1052] The obtained 4-fluorophenylpropan-1-ol (4.83 g, 31.3 mmol) wasdissolved in dichloromethane (50 ml), and triethylamine (6.55 ml, 47.0mmol) and methanesulfonyl chloride (2.91 ml, 37.6 mmol) were addedthereto in the ice bath followed by stirring under a nitrogen atmospherefor 30 minutes. The reaction mixture was diluted with dichloromethane(50 ml), and washed with 10% hydrochloric acid and subsequently with asaturated aqueous sodium chloride solution, and then dried overmagnesium sulfate. The solvent was evaporated in vacuo, and the residuewas dissolved in acetone (100 ml), and then sodium iodide (9.39 g, 62.6mmol) was added thereto followed by stirring under a nitrogen atmospherefor 2 hours at 50° C. The reaction mixture was diluted with ethylacetate (250 ml), and washed with 10% aqueous sodium thiosulfatesolution and subsequently with a saturated aqueous sodium chloridesolution, and then dried over magnesium sulfate. The solvent wasevaporated in vacuo, and the residue was purified by flashchromatography on a silica gel column (elution solvent; hexane:ethylacetate=5:1−2:1) to afford 4-fluorophenyl-1-iodopropane (7.12 g, 86%yield) as a yellow oil.

[1053] To hexamethylphosphoramide (20 ml) was added a suspension (50 ml)of 18% sodium acetylide in xylene, and an anhydrous dimethylformamide(20 ml) solution of 4-fluorophenyl-1-iodopropane (7.00 g, 26.5 mmol)obtained above was added thereto in the ice bath. The reaction mixturewas stirred for 2 hours at room temperature, and ice-cold water wascarefully poured thereto in the ice bath, and then the mixture wasextracted with ethyl acetate. The organic layer was washed with asaturated aqueous sodium chloride solution, and dried over magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by flash chromatography on a silica gel column(elution solvent; hexane) to give the title compound (2.67 g, 62% yield)as a colorless oil.

[1054] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 1.82(2H, m), 1.99 (1H, t, J=2.6 Hz), 2.19 (2H, m), 2.71 (2H, t, J=7.5 Hz),6.97 (2H, m), 7.14 (2H, m) Mass spectrum (EI) m/z: 162 (M⁺)

REFERENCE EXAMPLE 5 5-(4-Methoxyphenyl)pent-1-yne

[1055] The title compound was obtained using3-(4-methoxyphenyl)-1-iodopropane and sodium acetylide according to asimilar procedure to that described in Reference example 4.

[1056] Nuclear magnetic resonance spectrum (500 MHz, CDCl₃) δ ppm:1.78-1.88 (2H, m), 1.98 (1H, t, J=2.6 Hz), 2.15-2.22 (2H, m), 2.67 (2H,t, J=7.5 Hz), 3.79 (3H, s), 6.83 (2H, d, J=8.6 Hz), 7.11 (2H, d, J=8.6Hz) Mass spectrum (EI) m/z: 174 (M⁺)

REFERENCE EXAMPLE 6 5-Phenylpent-1-yne

[1057] The title compound was obtained using 3-phenyl-1-iodopropane andsodium acetylide according to a similar procedure to that described inReference example 4.

[1058] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:1.81-1.89 (2H, m), 1.99 (1H, t, J=2.8 Hz), 2.21 (2H, dt, J=2.8, 7.6 Hz),2.74 (2H, t, J=7.6 Hz), 7.16-7.23 (3H, m), 7.26-7.32 (2H, m) Massspectrum (EI) m/z: 144 (⁺)

REFERENCE EXAMPLE 7 5-Cyclohexylpent-1-yne

[1059] The title compound was obtained using 3-cyclohexyl-1-iodopropaneand sodium acetylide according to a similar procedure to that describedin Reference example 4.

[1060] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:0.75-1.38 (13H, m), 1.48-1.59 (2H, m), 1.94 (1H, t, J=2.8 Hz), 2.16 (2H,dt, J=2.8, 7.2 Hz) Mass spectrum (EI) m/z: 150 (M⁺)

REFERENCE EXAMPLE 8 4-(4-Fluorophenyloxy)but-1-yne

[1061] 4-Fluorophenol (5.00 g, 44.6 mmol), 3-butyn-1-ol (3.38 ml, 44.6mmol), and triphenylphosphine (17.5 g, 66.9 mmol) were dissolved intetrahydrofuran (100 ml), and diethyl azodicarboxylate (11.7 g, 66.9mmol) was added thereto in an ice bath followed by stirring for 18 hoursat room temperature. After the solvent was concentrated in vacuo, hexane(200 ml) and ethyl acetate (20 ml) were added thereto, and the resultingprecipitate was filtered out, and then the filtrate was concentrated invacuo. The obtained residue was purified by flash chromatography on asilica gel column (elution solvent; hexane:ethyl acetate=1:0) to affordthe title compound.

[1062] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 2.05(1H, t, J=2.7 Hz), 2.63-2.70 (2H, m), 4.07 (2H, t, J=7.0 Hz), 6.82-6.90(2H, m), 6.94-7.02 (2H, m) Mass spectrum (EI) m/z: 164 (M⁺)

REFERENCE EXAMPLE 9 3-(4-Methylphenyloxy)-1-propyne

[1063] The title compound was obtained using 4-methylphenol andpropargyl alcohol according to a similar procedure to that described inReference example 8.

[1064] Nucclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 2.29(3H, s), 2.50 (1H, t, J=2.4 Hz), 4.67 (2H, d, J=2.4 Hz), 6.88 (2H, d,J=8.4 Hz), 7.10 (2H, d, J=8.4 Hz) Mass spectrum (EI) m/z: 146 (M⁺)

REFERENCE EXAMPLE 10 3-[(4-Methylthio)phenyloxy]-1-propyne

[1065] The title compound was obtained using 4-(methylthio)phenol andpropargyl alcohol according to a similar procedure to that described inReference example 8.

[1066] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 2.45(3H, s), 2.52 (1H, t, J=2.4 Hz), 4.68 (2H, d, J=2.4 Hz), 6.93 (2H, d,J=8.9 Hz), 7.27 (2H, d, J=8.9 Hz) Mass spectrum (EI) m/z: 178 (M⁺)

REFERENCE EXAMPLE 11 3-(3-Methoxyphenyloxy)-1-propyne

[1067] The title compound was obtained using 3-methoxyphenol andpropargyl alcohol according to a similar procedure to that described inReference example 8.

[1068] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 2.52(1H, t, J=2.4 Hz), 3.79 (3H, s), 4.67 (2H, d, J=2.4 Hz), 6.53-6.60 (3H,m), 7.16-7.23 (1H, m) Mass spectrum (EI) m/z: 162 (M⁺)

REFERENCE EXAMPLE 12 3-(3,4-Dimethylphenyloxy)-1-propyne

[1069] The title compound was obtained using 3,4-dimethylphenol andpropargyl alcohol according to a similar procedure to that described inReference example 8.

[1070] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 2.20(3H, s), 2.24 (3H, s), 2.49 (1H, t, J=2.4 Hz), 4.65 (2H, d, J=2.4 Hz),6.72 (1H, dd, J=2.4, 8.0 Hz), 6.78 (1H, d, J=2.4 Hz), 7.04 (1H, d, J=8.0Hz) Mass spectrum (EI) m/z: 160 (M⁺)

REFERENCE EXAMPLE 13 4-(4-Methylphenyloxy)but-1-yne

[1071] The title compound was obtained using 4-methylphenol and3-butyn-1-ol according to a similar procedure to that described inReference example 8.

[1072] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm: 2.03(1H, t, J=2.8 Hz), 2.28 (3H, s), 2.66 (2H, dt, J=2.8, 7.2 Hz), 4.07 (2H,t, J=7.2 Hz), 6.81 (2H, d, J=8.8 Hz), 7.08 (2H, d, J=8.8 Hz) Massspectrum (EI) m/z: 160 (M⁺)

REFERENCE EXAMPLE 14 4-Cyclohexyloxybut-1-yne

[1073] To anhydrous dichloromethane (950 ml) were added cyclohexanone(32 ml, 0.31 mol), 1, 3-propanediol (33.5 ml, 0.46 mol), triethylorthoformate (51.5 ml, 0.31 mol), and zirconium chloride (1.44 g, 6.18mmol) followed by stirring under a nitrogen atmosphere for 1 hour atroom temperature. An ice-cold 1N aqueous sodium hydroxide solution (1.5l) was added to the reaction mixture, and the reaction solution wasextracted with dichloromethane, and then the dichloromethane layer waswashed with water. The dichloromethane layer was dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by distillation under reduced pressure to givecyclohexanone trimethyl ketal (26.8 g, 55% yield). To the suspension ofzirconium-chloride (24.9 g, 0.11 mol) in tetrahydrofuran (500 ml) wasslowly added sodium borohydride (20.5 g, 0.54 mmol) under a nitrogenatmosphere followed by stirring for 20 minutes at room temperature. Asolution of tetrahydrofuran (170 ml) including cyclohexanone trimethylketal (16.9 g, 0.11 mol) obtained above was added dropwise in a nitrogenatmosphere to the reaction solution in an ice bath. After the end ofdropping, the reaction solution was stirred overnight at roomtemperature. To this reaction solution was added ice-cold 2Nhydrochloric acid (600 ml) in the ice bath to stop the reaction, andtetrahydrofuran was evaporated in vacuo. The water layer residue wasextracted with ethyl acetate, and the ethyl acetate layer was washedwith a saturated aqueous sodium chloride solution. The ethyl acetatelayer was dried over anhydrous sodium sulfate, and the solvent wasevaporated in vacuo. The obtained residue was purified by chromatographyon a silica gel column (elution solvent; hexane:ethyl acetate=10:1−5:2)to afford 3-cyclohexyloxypropan-1-ol (13.4 g, 78% yield).

[1074] The obtained 3-cyclohexyloxypropan-1-ol (11.5 g, 72.9 mmol) wasdissolved in dichloromethane (240 ml), and then molecular sieve 4 Å (58g) and pyridinium chlorochromate (23.8 g, 0.11 mol) were added theretoin the ice bath followed by stirring under a nitrogen atmosphere for 1hour and 40 minutes. The reaction solution was diluted with ether, andthen the solution was filtered through Celite. The Celite was washedwith diethyl ether, and this filtrate was added to the previousfiltrate. The total filtrate was evaporated in vacuo, and the residuewas purified roughly by chromatography on a silica gel column (elutionsolvent; n-hexane:ethyl acetate=20:1−10:1) to give a crude3-cyclohexyloxypropionaldehyde (8.6 g).

[1075] A dichloromethane solution (120 ml) of triphenylphosphine (57.7g, 0.22 mol) in an ice bath were added dropwise to the dichloromethanesolution (120 ml) including carbon tetrabromide (36.5 g, 0.11 mol) undera nitrogen atmosphere. After the end of dropping, the reaction mixturewas stirred for 5 more minutes. To the reaction solution in the ice bathwas added dropwise under a nitrogen atmosphere a dichloromethanesolution (90 ml) of the crude 3-cyclohexyloxypropionaldehyde (8.6 g)obtained above, and after dropping, the reaction mixture was stirred for25 more minutes. The reaction solution was diluted with dichloromethane,and washed with a saturated aqueous sodium hydrogencarbonate solutionand then with a saturated aqueous sodium chloride solution. After thedichloromethane layer was dried over anhydrous sodium sulfate, thesolvent was evaporated in vacuo. The residue was purified bychromatography on a silica gel column (elution solvent; hexane:ethylacetate=100:1−33:1) to afford 4-cyclohexyloxy-1,1-dibromobut-1-ene (12.6g, 55% yield, 2 processes).

[1076] To a tetrahydrofuran solution (130 ml) of4-cyclohexyloxy-1,1-dibromobut-1-ene (12.6 g, 40.4 mmol) obtained above,was added dropwise under a nitrogen atmosphere at −78° C. the hexanesolution of 1.5N n-butyllithium (54 ml, 81.0 mmol). After the end ofdropping, the reaction solution was stirred for 1 hour, and then warmedup gradually to room temperature. After the reaction solution wasstirred at room temperature for 50 minutes, water was added thereto inthe ice bath to terminate the reaction. The resulting reaction solutionwas extracted with diethyl ether, and the diethyl ether layer was washedwith the saturated aqueous sodium chloride solution. The diethyl etherlayer was dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified bychromatography on a silica gel column (elution solvent; hexane:ethylacetate=100:1−50:1) to give the title compound (4.35 g, 71% yield).

[1077] Nuclear magnetic resonance spectrum (400 MHz, CDCl₃) δ ppm:1.13-1.36 (5H, m), 1.48-1.58 (1H, m), 1.67-1.81 (2H, m), 1.85-1.95 (2H,m) 1.97 (1H, t, J=2.8 Hz), 2.45 (2H, dt, J=2.8, 7.2 Hz), 3.23-3.32 (1H,m), 3.59 (2H, t, J=7.2 Hz) Mass spectrum (EI) m/z: 153 (M+H)⁺

TEST EXAMPLE 1

[1078] Determination of the Inhibitory Activity Against Host VersusGraft Reaction (HvGR) in the Rat.

[1079] (1) Two Strains of Rats (Lewis Rats (Male, 6 Weeks Old, CharlesRiver Japan) and WKAH/Hkm (Male, 7 Weeks Old, SLC Japan)) Were Used.Five Rats (Host) Per Group Were Used.

[1080] (2) Induction of HvGR

[1081] The spleen cells were isolated from the spleen of the rats and1×10⁸ cells were suspended in the RPMI640 medium (LIFE TECHNOLOGIES,Rockville Md. USA). One hundred microliter (1×10⁷ cells) of the spleencell suspension whose cells were isolated from either WKAH/Hkm rats orLewis rats were subcutaneously injected into the bilateral feet pad ofthe hindlimbs of the Lewis rat.

[1082] (3) Administration of the Compound

[1083] The compound was suspended in 0.5% tragacanth solution. Thesuspended compound was orally administered to rats in the drug-treatedgroup (Lewis rats injected with spleen cells isolated from AH/Hkm rats,and treated with the compound) at a volume of 5 ml/kg. The treatment wasstarted on the day of the spleen cell injection, once a day, for 4successive days. Tragacanth solution (0.5%) was orally administered,instead of the suspension of the test compound, to the rats in the samestrain group (Lewis rats injected with spleen cells which were isolatedfrom the Lewis rats) and to the rats in the control group (Lewis ratsinjected spleen cells isolated from WKAH/Hkm rats, and not treated withthe test compound).

[1084] (4) Determination Procedures for Inhibitory Activity against HvGR

[1085] The average weight of the popliteal lymph node of the same strainrats was subtracted from the weight of the popliteal lymph node of theindividual rat (popliteal lymph gland weight due to HvGR). Theinhibition rate of the popliteal lymph node weight due to HvGR of theindividual rat treated with the test compound against the average weightof the control rats was calculated. The inhibitory activity of the testcompound was expressed as an ID50 value (mg/kg) calculated from thedose-inhibition rate by the least square method.

[1086] As the results of the present experiment, the compound of thepresent invention showed an excellent inhibitory activity against HvGRin the rat. TABLE 5 Test Compounds HvGR ID50 values (mg/kg) Example 10.0843 Example 11 0.0844 Example 40 0.0683 Example 43 0.0730 Example 460.0454 Reference Compound 1 0.354

TEST EXAMPLE 2

[1087] Determination of the Inhibitory Activity of the Compounds of thePresent Invention on Induction of Adjuvant Arthritis

[1088] 1. Preparation of Adjuvant

[1089] Heat-killed, Mycobacterium butylricum was suspended-in mineraloil at a concentration of 2 mg/ml and sonicated with an ultrasonicapparatus.

[1090] 2. Preparation of the Test Compound.

[1091] The test compound was suspended in 0.5% Tragacanth solution.

[1092] 3. Induction of Adjuvant Arthritis

[1093] The adjuvant prepared as described in 1 was intradermallyinjected into the right hind paw of the female rats (usually Lewis ratswere used) at a volume of 0.05 ml. Five rats per group were used. In onegroup of rats, adjuvant was not injected for the control group.

[1094] 4. Administration of the Compound

[1095] The compound solution prepared as described in 2 was orallyadministered to rats from the injection day of the adjuvant, once dailyfor 21 days, at a dose of 5 ml/kg. Tragacanth solution (0.5%) was orallyadministered to one group of rats treated with adjuvant (the controlgroup) and also to rats not treated with adjuvant.

[1096] 5. Calculation Methods of Inhibitory Activity of the Compound

[1097] The volume of the right hind paw was determined with aplethymometer. The volume of the intact paw was subtracted from theindividual volume, and the difference was used as the swelling volume.Then the inhibitory activity of the compound was calculated from theindividual swelling volume of rats treated with the compound and that inthe swelling volume of the control rats. The ID50 value of the compoundwas obtained from the doses treated and the average inhibitory rate ofthe group.

[1098] From the present experiment, the compound in the presentinvention showed a potent inhibitory activity. TABLE 6 Compound ID50value (mg/kg) Test Example 1 0.0897 Test Example 34 0.0470 ReferenceCompound 0.1666

What is claimed is:
 1. A compound of formula (La) or (Lb):

wherein: R¹ and R² are the same or different and each represents ahydrogen atom or an amino protecting group; R^(3a) represents a hydrogenatom or a hydroxy protecting group or when R¹ is a hydrogen atom; R² andR^(3a), taken together form a group of formula —(C═O)—; R^(4a)represents a C₁-C₂₀ alkyl group, a C₂-C₂₀ alkyl group interrupted with aheteroatom(s), a C₁-C₂₀ alkyl group substituted with an aryl group(s) ora heteroaryl group(s), a C₂-C₂₀ alkynyl group, a C₃-C₂₀ alkynyl groupinterrupted with a heteroatom(s), a C₂-C₂₀ alkynyl group substitutedwith an aryl group(s) or a heteroaryl group(s), a C₂-C₂₀ alkenyl group,a C₃-C₂₀ alkenyl group interrupted with a heteroatom(s), a C₂-C₂₀alkenyl group substituted with an aryl group(s) or a heteroarylgroup(s), a C₂-C₂₀ alkyl group which is substituted with an arylgroup(s) or a heteroaryl group(s) and interrupted with a heteroatom(s),or a cycloalkyl group; m represent an integer from 0 to 4; Ar representsan aryl group, a heteroaryl group, an aryl group substituted with 1 to 5substituents selected from substituent group a, a heteroaryl groupsubstituted with 1 to 5 substituents selected from substituent group a,with the proviso that when Ar is an aryl group, R¹ is not a hydrogenatom and R² and/or R^(3a) do not represent a hydrogen atom; whereinsubstituent group a represents a halogen atom, a lower alkyl group, ahalogenated lower alkyl group, a lower alkoxy group, a lower alkylthiogroup, a carboxyl group, a lower alkoxycarbonyl group, a hydroxyl group,a lower aliphatic acyl group, an amino group, a lower mono-alkylaminogroup, a lower di-alkylamino group, a lower aliphatic acylamino group, acyano group, and a nitro group.
 2. A compound according to claim 1wherein said compound has a formula (La).
 3. A compound according toclaim 1 or 2 wherein R¹ is a hydrogen atom.
 4. A compound according toclaim 1 or 2 wherein R² and R^(3a) taken together form a group offormula —(C═O)—.
 5. A compound according to claim 1 or 2 wherein R^(3a)is a hydrogen atom.
 6. A compound according to claim 1 or 2 whereinR^(4a) is a C₁-C₁₀ alkyl group, a C₂-C₁₀ alkyl group interrupted with aheteroatom(s), a C₁-C₁₀ alkyl group substituted with an aryl group(s) ora heteroaryl group(s), a C₂-C₁₀ alkynyl group, a C₃-C₁₀ alkynyl groupinterrupted with a heteroatom(s), a C₂-C₁₀ alkynyl group substitutedwith an aryl group(s) or a heteroaryl group(s), a C₂-C₁₀ alkenyl group,a C₃-C₁₀ alkenyl group interrupted with a heteroatom(s), a C₂-C₁₀alkenyl group substituted with an aryl group(s) or a heteroarylgroup(s), a C₂-C₁₀ alkyl group which is substituted with an arylgroup(s) or a heteroaryl group(s) and interrupted with a heteroatom(s),or a C₅-C₁₀ cycloalkyl group.
 7. A compound according to claim 1 or 2wherein R^(4a) is a C₁-C₁₀ alkyl group, a C₂-C₁₀ alkyl group interruptedwith a heteroatom(s), a C₁-C₁₀ alkyl group substituted with an arylgroup(s) or a heteroaryl group(s), a C₂-C₁₀ alkynyl group, a C₂-C₁₀alkenyl group, or a C₅-C₁₀ cycloalkyl group.
 8. A compound according toclaim 1 or 2 wherein R^(4a) is a C₁-C₁₀ alkyl group.
 9. A compoundaccording to claim 1 or 2 wherein R^(4a) is a C₁-C₆ alkyl group.
 10. Acompound according to claim 1 or 2 wherein R^(4a) is a methyl group oran ethyl group.
 11. A compound according to claim 1 or 2 wherein Ar is aphenyl, furyl, thienyl, benzothienyl group, or a phenyl, furyl, thienyl,or benzothienyl group, said groups optionally being substituted with 1to 4 substituents selected from substituent group a.
 12. A compoundaccording to claim 1 or 2 wherein Ar is a thienyl group or a thienylgroup substituted with 1 to 4 substituents selected from substituentgroup a.
 13. A compound according to claim 1 or 2 wherein Ar is abenzothienyl group or a benzothienyl group substituted with 1 to 4substituents selected from substituent group a.
 14. A compound accordingto claim 1 or 2 wherein m is 0 or
 1. 15. A compound according to claim 1or 2 wherein substituent group a is a halogen atom, a hydroxyl group, alower alkyl group, a halogenated lower alkyl group, a lower alkoxygroup, a carboxyl group, a lower aliphatic acyl group, a lower aliphaticacylamino group, an amino group, a cyano group, or a nitro group.
 16. Acompound according to claim 1 or 2 wherein R¹ is a hydrogen atom; R² andR^(3a) taken together form a group of formula —(C═O)—; R^(3a) is ahydrogen atom; R^(4a) is a C₁-C₁₀ alkyl group, a C₂-C₁₀ alkyl groupinterrupted with a heteroatom(s), a C₁-C₁₀ alkyl group substituted withan aryl group(s) or a heteroaryl group(s), a C₂-C₁₀ alkynyl group, aC₃-C₁₀ alkynyl group interrupted with a heteroatom(s), a C₂-C₁₀ alkynylgroup substituted with an aryl group(s) or a heteroaryl group(s), aC₂-C₁₀ alkenyl group, a C₃-C₁₀ alkenyl group interrupted with aheteroatom(s), a C₂-C₁₀ alkenyl group substituted with an aryl group(s)or a heteroaryl group(s), a C₂-C₁₀ alkyl group which is substituted withan aryl group(s) or a heteroaryl group(s) and interrupted with aheteroatom(s), or a C₅-C₁₀ cycloalkyl group; m is 0 or 1; Ar is aphenyl, furyl, thienyl, benzothienyl group, or a phenyl, furyl, thienyl,or benzothienyl group, said groups optionally being substituted with 1to 4 substituents selected from substituent group a; and substituentgroup a is a halogen atom, a hydroxyl group, a lower alkyl group, ahalogenated lower alkyl group, a lower alkoxy group, a carboxyl group, alower aliphatic acyl group, a lower aliphatic acylamino group, an aminogroup, a cyano group, or a nitro group.
 17. A compound according toclaim 16 wherein R^(4a) is a C₁-C₁₀ alkyl group, a C₂-C₁₀ alkyl groupinterrupted with a heteroatom(s), a C₁-C₁₀ alkyl group substituted withan aryl group(s) or a heteroaryl group(s), a C₂-C₁₀ alkynyl group, aC₂-C₁₀ alkenyl group, or a C₅-C₁₀ cycloalkyl group; and Ar is a thienylgroup or a thienyl group substituted with 1 to 4 substituents selectedfrom substituent group a.
 18. A compound according to claim 16 whereinR^(4a) is a C₁-C₁₀ alkyl group; and Ar is a benzothienyl group or abenzothienyl group substituted with 1 to 4 substituents selected fromsubstituent group a.
 19. A compound according to claim 16 wherein R^(4a)is a C₁-C₆ alkyl group; and Ar is a benzothienyl group or a benzothienylgroup substituted with 1 to 4 substituents selected from substituentgroup a.
 20. A compound according to claim 18 wherein R^(4a) is a methylgroup or an ethyl group; and Ar is a benzothienyl group or abenzothienyl group substituted with 1 to 4 substituents selected fromsubstituent group a.
 21. A compound according to claim 18 wherein R¹ isa hydrogen atom; R² and R^(3a) taken together form a group of formula—(C═O)—; R^(3a) is a hydrogen atom; R^(4a) is a methyl group or an ethylgroup; Ar is a benzothienyl group or a benzothienyl group substitutedwith 1 to 4 substituents selected from substituent group a.
 22. Aprocess for the preparation of a compound of a formula (XLIVa) or(XLIVb)

wherein: R¹ and R² are the same or different and each represents ahydrogen atom or an amino protecting group; R^(4a) represents a C₁-C₂₀alkyl group, a C₂-C₂₀ alkyl group interrupted with a heteroatom(s), aC₁-C₂₀ alkyl group substituted with an aryl group(s) or a heteroarylgroup(s), a C₂-C₂₀ alkynyl group, a C₃-C₁₀ alkynyl group interruptedwith a heteroatom(s), a C₂-C₂₀ alkynyl group substituted with an arylgroup(s) or a heteroaryl group(s), a C₂-C₂₀ alkenyl group, a C₃-C₂₀alkenyl group interrupted with a heteroatom(s), a C₂-C₂₀ alkenyl groupsubstituted with an aryl group(s) or a heteroaryl group(s), a C₂-C₂₀alkyl group which is substituted with an aryl group(s) or a heteroarylgroup(s) and interrupted with a heteroatom(s), or a cycloalkyl group;and R¹¹ has the same meaning as that indicated above for R^(4a); whichprocess comprises the selective acylation of one hydroxyl group of a2-substituted 2-amino-1,3-propanediol derivative of formula (XLII)

(wherein R¹, R² and R^(4a) are as defined above) with a carboxylic acidester derivative of formula (XLIII) R¹¹COOCH═CH₂   (XLIII) (wherein R¹¹is as defined above) in the presence of a lipase to afford a2-substituted 2-amino-1,3-propanediol mono-ester derivative of formula(XLIVa) or (XLIVb).
 23. A process for preparation according to claim 22wherein one of R¹ and R² is a hydrogen atom and the other one is anamino protecting group.
 24. A process for preparation according to claim22 or 23 wherein R^(4a) is a C₁-C₁₀ alkyl group, a C₂-C₁₀ alkyl groupinterrupted with a heteroatom(s), a C₁-C₁₀ alkyl group substituted withan aryl group(s) or a heteroaryl group(s), a C₂-C₁₀ alkynyl group, aC₃-C₁₀ alkynyl group interrupted with a heteroatom(s), a C₂-C₁₀ alkynylgroup substituted with an aryl group(s) or a heteroaryl group(s), aC₂-C₁₀ alkenyl group, a C₃-C₁₀ alkenyl group interrupted with aheteroatom(s), a C₂-C₁₀ alkenyl group substituted with an aryl group(s)or a heteroaryl group(s), a C₂-C₁₀ alkyl group which is substituted withan aryl group(s) or a heteroaryl group(s) and interrupted with aheteroatom(s), or a C₅-C₁₀ cycloalkyl group.
 25. A process forpreparation according to claim 22 or 23 wherein R^(4a) is a C₁-C₁₀ alkylgroup, a C₂-C₁₀ alkyl group interrupted with a heteroatom(s), a C₁-C₁₀alkyl group substituted with an aryl group(s) or a heteroaryl group(s),a C₂-C₁₀ alkynyl group, a C₂-C₁₀ alkenyl group, or a C₅-C₁₀ cycloalkylgroup.
 26. A process for preparation according to claim 25 wherein R¹¹is a C₁-C₂₀ alkyl group, or a C₁-C₂₀ alkyl group substituted with anaryl group(s) or a heteroaryl group(s).
 27. A process for preparationaccording to claim 24 wherein R¹¹ is a C₁-C₂₀ alkyl group, or a C₁-C₂₀alkyl group substituted with an aryl group(s) or a heteroaryl group(s).28. A process for preparation according to claim 22 or 23 wherein R¹¹ isa C₁-C₂₀ alkyl group, or a C₁-C₂₀ alkyl group substituted with an arylgroup(s) or a heteroaryl group(s).